disease-modifying therapies in frontotemporal lobar degeneration

1008 Current Medicinal Chemistry, 2012, 19, 1008-1020

0929-8673/12 $58.00+.00 © 2012 Bentham Science Publishers

Disease-Modifying Therapies in Frontotemporal Lobar Degeneration

B. Bigni, E. Premi, A. Pilotto, A. Padovani and B. Borroni*

Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Italy Abstract: Frontotemporal Lobar Degeneration (FTLD) is characterized by behavioral changes, executive dysfunctions, and language impairment, sustained by different neuropathological patterns. The collective efforts of clinical, pathological and genetic studies have recently opened new insights into the underpinnings of pathological mechanisms of this complex disorder. Different types of inclusions define the new conceptual framework for FTLD classification. Up to now, Tau (FTLDTau-positive), TAR DNA-binding protein (TDP43, FTLD Tau-negative TDP43-positive) have been recognized as the most frequent neuropathological hallmarks of FTLD. In some clinical cases, monogenic forms are identified, mainly due to Microtubule Associated Protein (MAPT) or Granulin (GRN) mutations.

No treatments for FTLD are available yet, and off-label medications are commonly used to treat behavioralsymptoms. However, several studies testing potential modifying treatments on the basis of neuropathological inclusions are ongoing. With regard to FTLD-Taupositive, inhibitors of Tau kinases or manipulation of Tau-processing pathways have been proposed. On the other hand, progranulin haploinsuffciency associated with GRN mutations, has been counteracted by specific pharmacological treatments. Finally, new insights into pathological processing of TDP-43 and other key-molecules involved in FTLD, such as hyperphosphorylation and ubiquitination, and their consequent translocation from nucleus to cytoplasm, and their role as RNA-binding proteins, open new perspectives for a growing number of potential therapeutic targets. In this continuously evolving field, the aim of the present review is to summarize the new findings on molecular targets and modifying therapies in FTLD.

Keywords: Frontotemporal Lobar Degeneration, Frontotemporal Dementia, treatment, therapies, Tau, Progranulin.

INTRODUCTION

Frontotemporal Lobar Degeneration (FTLD) represents the second most common cause of presenile dementia, accounting for 20% of all cases under the age of 65 years [1]. Brain pathology is characterized by predominantly frontal and/or temporal atrophy with different types of pathologic accumulations, namely tau, TAR DNA-binding protein (TDP-43) and Fused-in-Sarcoma (FUS). With regard to clinical presentation three distinct variants have been described. Behavioral variant Frontotemporal Dementia (bvFTD) is mainly characterized by alteration in personality and social conduct, with frontal damage often prevalent on the right side [2-6]. Progressive Nonfluent Aphasia (PNFA) is a disorder of expressive language with slow rate of speech, phonologic and grammatical errors, as well as difficulties in reading and writing [7]; brain atrophy is predominantly in left frontal operculum, premotor and supplementary premotor areas and anterior insula [8].

Semantic Dementia (SD), is characterized by fluent, anomic aphasia and behavioural changes, with often asymmetric degeneration of the temporal poles and white matter damage (inferiorlongitudinal fasciculus) [9].

With a high rate of positive family history (up to 40%), approximately 10% of FTLD patients show an autosomal dominant pattern of inheritance [10]. The last fifteen years have been marked by the discovery of different causal genes for FTLD. In 1998, Microtuble Associated Protein Tau (MAPT), encoding for protein tau was identified as the causal gene in FTDP-17 families with tau-positive histopathology [11].

Almost ten years later, Granulin (GRN) gene mutations were identified in FTDP-17 families with tau-negative histopathology [12,13].

More recently, mutations in TARDP gene and FUS gene were shown to be associated with familial Amyotrophic Lateral Sclerosis (ALS) and FTLD [14-17]. MAPT and GRN mutations account for the majority of familial FTLD cases (http://www.molgen.ua.ac.be/ FTDMutations).

There is no unique relationship between clinical phenotype, i.e. bvFTD, PNFA or SD, and protein dysfunction, i.e. tau, TDP-43 or

*Address correspondence to this author at the Neurology Unit, University of Brescia, Piazza Spedali Civili, 1, 25125 Brescia, Italy; Tel: 0039 0303995632; Fax: 0039 0303995027; E-mail: [email protected]

FUS. Recent neuropathological classifications have highlighted the complex multimodal relationship between phenotypic presentation and the underlying neuropathology [18]. All cases of FTLD can be subclassified into the following four major categories, which are based on the presence or the absence of specific inclusion bodies: (i) FTLD with tau inclusions (FTLD-TAU), (ii) FTLD with tau-negative, ubiquitin and TDP-43-positive inclusions (FTLD-TDP) and (iii) FTLD with tau/TDP-43 negative and FUS-positive inclusions (FTLDFUS), (iv) FTLD with positive immunohisto-chemistry against proteins of the ubiquitin proteasome system (FTLD-UPS).

Two different approaches might be taken to treat FTLD. On one hand, symptomatic treatments based on the clinical presentation of FTLD and related behavioural symptoms, on the other, disease-modifying pharmacological interventions depending on causal molecular pathways.

Nowadays, no specific pharmacological interventions for FTLD are available. However, data derived from the literature, show that many promising drugs, although initially designed for other conditions, could play a neuroprotective role [19], and several clinical trials on pharmacological interventions are ongoing (www.clinicaltrial.gov) (www.clinicaltrialsregister.eu) (see Table1).

From this perspective, the identification of biomarkers, biologically related to neuropathological process is mandatory for testing potential disease-modifying therapies [20-22].

In the present review, we discuss the current available pharmacological interventions for FTLD, covering empiric strategies, Tau-based approaches and the approaches based on new molecular targets.

NEUROTRASMISSION SYSTEM IMPAIRMENT IN FTLD: LOOKING FOR EMPIRIC INTERVENTION

Different classes (types) of drugs commonly used in other diseases, such as psychiatric and other neurodegenerative disorders, have been tested, on the basis of impaired neurotransmitter dysfunction. Evidence suggests that several neurotransmitter pathways, i.e. the cholinergic, serotonergic, dopaminergic and glutamatergic, may be defective in FTLD.

Disease-Modifying Therapies in Frontotemporal Lobar Degeneration Current Medicinal Chemistry, 2012 Vol. 19, No. 7 1009

Cholinergic System

Current findings are controversial on a significant involvement of the cholinergic system in FTLD. Most studies report no functional impairment, with normal or increased level of cortical choline acetyltransferase [23-25] and normal level of acetylcholinesterase [26]. Neurons in the nucleus basalis of Meynert appear to be preserved [27] and isolated reports refer to a slight alteration in the cholinergic system [28].

However, despite lack of clear-cut findings, given their beneficial effect in Alzheimer’s disease, one of the first drugs tested on patients with FTLD, was acetylcholinesterase inhibitors, supporting cholinergic deficit in FTLD [23]. Different studies have evaluated their possible role in cognitive performance and behavioral disturbances in FTLD patients. No significant improvement on cognition was found. Some reports claimed a positive effect on behavioral symptoms, others showed no benefit (with a slight increase of disinhibition and compulsive behavior) [29,30].

The main biases of all these studies were the sample size and the open-label study design.

Serotoninergic System

The involvement of the serotoninergic system in FTLD has been well documented, as postsynaptic 5-HT1 and 5-HT2 serotonin receptor depletion in frontal cortex has been described [24,25,31,32].

These findings gave the rationale for the utilization of selective serotonin reuptake inhibitors (SSRI) to treat behavioural symptoms, i.e. depression, compulsions and disinhibition [33]. Once again, the vast majority of the clinical trials were biased by small sample size and absence of placebo control group. A meta-analysis on four different antidepressants (trazodone, selegiline, fluvoxamine and

paroxetine) suggested that the use of serotoninergic drugs was associated with a significant reduction of behavioral disturbances measured by Neuropsychiatric Inventory Scale (NPI) [34]. However, considering the small sample size of the studies and the different pharmacological interventions did not allow an effective comparison between these studies. The role of trazodone, which acts as low affinity serotonin reuptake inhibitor and also as alpha-1 and alpha-2 adrenergic receptor antagonist, was found to improve behavioral disturbances but not cognitive performances [35].

Dopaminergic System

A deficit of the dopaminergic system in FTLD has been suggested clinically by the frequent presence of an extrapyramidal syndrome at the onset or during progression disease. Furthermore, a reduction of D2 ligand uptake in the frontal cortex was observed [36], even if not further confirmed [37,38].

Thus, in line with their role in increasing the availability of dopamine, monoamine oxidase inhibitors (MAO) have been tested in FTLD. Both MAO-A (like moclobemide) and MAO-B (selegiline) inhibitors presented promising results on neuropsychiatric symptoms with likely potential neuroprotective effect [39-42]. Larger randomized studies to confirm these initial reports are warranted.

Glutamatergic System

Several reports on a possible involvement of alpha-amino-3-hydroxy-5- methyl-4- isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors have been described [24]. In recent years, several reports have suggested a possible effect of memantine in modulating cognitive profile and behavioural disturbances in FTLD. However, at the moment only two clinical trials are available. An open-label study on 21 FTLD patients showed a transient improvement in total NPI scores, but no

Table 1. Ongoing Clinical Trials on Pharmacologic Agents in FTLD (www.clinicaltrial.gov) (www.clinicaltrialsregister.eu)

Clinical Trial Drugs Phase Expected Enrollment

Status Reference Centre Principal investigator

Type

Memantine (10mg BID) for the Frontal and Temporal Subtypes of FTLD

Memantine IV 140 Recruiting NCT00545974 University of California, USA

Boxer AL RDBPC

Safety Study of Intranasal Oxytocin in FTLD

Oxytocin I 24 Recruiting NCT01386333 Lawson Health Research Institute

Finger EC RDBPC

A Pilot Study to Explore the Safety and Tolerability of Galantamine HBr in FTLD

Galantamine I 41 Complete NCT00416169 Johnson & JohnsonPharmaceutical Research & Development, LLC

Johnson & Johnson

RDBPC

Open Label Pilot Study of the Effects of Memantine on FDG-PET in FTLD

Memantine I 15 Ongoing NCT00594737 Rotman Research Institute at Baycrest

Chow TW Safety Study

Effects of Tolcapone in FTLD Tolcapone II 30 Recruiting NCT00604591 Columbia University, USA

Huey E Safety Study

Davunetide (AL-108) in Predicted Tauopathies - Pilot Study

Davunetide I 12 Ongoing NCT01056965 UCLA, San Francisco, USA

Boxer AL Safety Study

Study to Evaluate the safety and efficacy of Davunetide for the Treatment of PSP

Davunetide I 300 Recruiting NCT01110720 Allon Therapeutics Boxer AL Safety Study

Effects of Coenzyme Q10 in PSP Coenzyme Q10

I 60 Recruiting NCT00382824 Lahey Clinic Apetauerova D Safety Study

Efficacy, Tolerability and Safety of Azilect in Subjects With PSP (PROSPERA)

Rasagiline III 112 Recruiting NCT01187888 Ludwig-Maximilians - University of Munich, Germany

Lorenzl S RDBPC

A Pilot Clinical Trial of Pyruvate, Creatine, and Niacinamide in PSP

Pyruvate, Creatine, and Niacinamide

I 20 Unknown NCT00605930 University of Louisville, USA

Litvan I RDBPC

RDBPC= Randomized Double-Blind Placebo Controlled Study; FTLD=Frontotemporal Lobar Degeneration; PSP=Progressive Sopranuclear Palsy.

1010 Current Medicinal Chemistry, 2012 Vol. 19, No. 7 Bigni et al.

improvement in cognition [43], and a double-blind placebo-controlled phase II trial on 49 patients reported no significant effect of memantine after one-year treatment [44]. More recently, an open-label study showed an increased brain metabolism in the salience network (defined as the frontal brain regions functionally connected in resting state neuroimaging studies and correlated with frontal functions, specifically impaired in FTLD) induced by memantine treatment [45]. The selective effect to promote language performances established by memantine could be a further element in testing this drug in language variant of FTLD [46].

TAU-RELATED PHARMACOLOGICAL APPROACHES

Tau protein is the longest known and best studied contributor in FTLD and the identification of mutations within MAPT gene (encoding for tau protein) has provided compelling evidence for its causative role in the disease. Tau inclusions are the most frequent pathology observed in FTLD, after TDP43 inclusions, and are also present in the other neurodegenerative diseases such as Alzheimer’sdisease [47,48].

The knowledge gained from studying FTLD and an increased understanding of how the posttranslational modifications of tau affect its function has led to a growing interest in developing drugs that target pathological tau [49] (see Fig. 1). In this direction, prevention of mis-splicing, hyperphosphorylation, aggregation, and clearance of tau aggregates are promising therapeutic targets for interferring with tau-induced toxicity and neurodegeneration.

Tau is a highly soluble protein of the class of natively unfolded proteins. In the adult human central nervous system, six tau isoforms are expressed by alternative splicing of exons 2-3 and 10 of MAPT gene (17q21.3). Tau isoforms differ by the presence of three or four repeats in the microtubule binding domain (3R or 4R). The number of repeats can modulate the affinity between tau and the microtubule surface. Thus, tau works as microtubule assembler and stabilizer [50,51].

In approximately half of patients carrying MAPT mutations, a twofold to sixfold excess of 4R tau over 3R isoforms was observed [11,52]. Tau mutations are either intronic, localized close to the splice-donor site following exon 10 and resulting in overproduction of 4R tau isoforms, or comprise missense, deletion, or silent mutations in the coding regions [11,48,53].

MAPT Splicing Modulators

Hence, shifting the tau isoform ratio from 4R to 3R isoforms by alternative splicing was proposed as a therapeutic option in tauopathies. Splice modifiers acting at the splice donor site of exon 10 (a stem-loop in the pre-mRNA) may change the isoform ratio, thus stabilizing the tau stem loop by decreasing inclusion of exon 10 and increasing expression of 3R tau [54,55].

The aminogycoside Neomycin can bind and stabilize the tau stem loop, eventhough this effect is rather non-specific, limiting its usefulness [56]. More recently Mitoxantrone has been identified as a loop stabilizer [57,58].

Fig. (1). Potential therapeutic approaches against tau-related neurodegenerative process. The figure sintetized the actual proposed approaches towards tau neuropathology. See text for details. NFT= neurofibrillary tangles. UPS= ubiquitine-proteasome system. MAPT= microtubule-associated protein tau. O-GlcNAcase= O-GlcNAcase enzyme.


Splicing-modifying drugs that bind directly to mRNA are nowadays of great interest [59-61].

Spliceosome-mediated RNA trans-splicing (SMarT) is another method for mRNA reprogramming and has been tested in cells transfectedwith tau [62,63].

Microtubule-Stabilizing Drugs

Most of the cases do not recognize genetic mutation defects and splicing-related dysregulation, but are characterized by tau abnormal aggregation. The causes of tau aggregation in sporadic tauopathies are not fully understood [64].

Tau is normally phosphorylated at multiple serine and threonine residues, and hyperphosphorylation reduces microtubule binding [65,66] and enhances aggregation [67,68]. Therefore, it is possible that changes in protein kinase or phosphatase activities could enhance tau phosphorylation with consequent loss-of-function or gain-of-function toxicities. Since tau-associated neuropathology is likely to result from reduced microtubule stabilization and/or the formation of toxic oligomers/fibrils, exploratory therapeutic strategies have been directed towards these mechanisms [69]. Additional post-translational modifications may also contribute to tau dysfunction.

Evidence for tau loss of function has been demonstrated in transgenic mice expressing the smallest wild-type human tau isoform [70,71]. These animals have reduced microtuble density and show motor impairment, which can be overcome by treatment with the microtublestabilizing agents, such as paclitaxel, an alkaloid of Taxus brevifolia [71,72].

Paclitaxel has been shown to reverse fast axonal transport deficits by functionally substituting tau [71]; however this approach has not successfully prevented neuronal death in a toxin-induced model of tauopathy [73]. As paclitaxel does not readily cross the blood–brain barrier, the changes observed presumably resulted from paclitaxel uptake at peripheral neuromuscular junctions and subsequent retrograde transport to spinal motor neurons.

Microtubule-stabilizing agents that cross the blood–brain barrier might lead to similar improvements in tauopathy [49].

The octapeptide containing the amino-acid sequence NAPVSIPQ (NAP, generic name davunetide), which crosses the blood–brain barrier, was found to promote microtubule assembly [74]. Intranasal NAP administration for 9 months to transgenic mice that develop A� and tau deposits resulted in a reduction in tau phosphorylation and A� levels. Furthermore, in older transgenic mice that had developed moderate pathology, NAP treatment reduced tau phosphorylation, although A� levels were unaffected [75,76].

While these studies provided important proof of principle, the approach towards compensating for loss of function mutations, will be the identification of drugs that have adequate central nervous system exposure without causing the peripheral side-effects, including myelo-suppression and neuropathy, which plague existing microtuble-directed oncology therapeutics [69].

Further analysis of microtubule-stabilizing compounds to identify those that can gain access to the brain, followed by testing in animal models of tauopathy, will provide further information on the efficacy and safety of this approach [49].

Tau Phoshorilation Inhibitors

The propensity of hyperphosphorylated tau to aggregate leading to tau gain of function, makes identification of kinase inhibitors a considerably therapeutic measure [77].

Several kinases are capable of phosphorylating tau in vitro, and a variety of data suggest that glycogen synthase kinase-3 (GSK-3),

cell-cycle dependent kinase-5 (CDK5), extracellular signalrelated kinase 2 (ERK2) and microtubule affinity-regulating kinase (MARK) may be the most relevant kinases in vivo [78-80].

A number of drug discovery initiatives have identified selective tau-kinase inhibitors as targets for treatment of Alzheimer Disease and other tauopathies [78,81]. As these kinases are involved in many cellular processes, it needs to be proven which ones are both safe and efficacious [69].

A small number of tau-kinase inhibitors have progressed to efficacy testing in animal models of tauopathy. Indeed, the development of several strains of transgenic mice that overexpress tau with FTLD17-associated mutations have provided important research tools for compound evaluation [82].

Most in vivo efficacy studies of tau-kinase inhibitors have examined the effects of GSK3 inhibition. The GSK-3 has two isoforms � and � encoded by two different genes. Both isoforms are involved in glucose metabolism, cell proliferation, wound signaling, and apoptosis [83]. GSK-3 co-localizes with neurofibrillary tangle-like brain lesions in trangenic mice [84] as well as with hyperphosphorylated tau deposits [85].

Lithium, a well-characterized mood-stabilizer, competes with magnesium for GSK-3 binding; in this view, it leads to reduced tau-phosphorylation, aggregation and axonal degeneration in transgenic mice [86,87]. However, a recent 10-week clinical trial of lithium in 71 patients with mild Alzheimer’s disease did not show any significant clinical or biomarker efficacy [88].

Beyond lithium, other GSK-3� inhibitors, blocking tau pathology, were investigated in transgenic mice in vivo that have increased tau phosphorylation compared with adult animals [89,90]. Several clinical trials with GSK-3� inhibitors, such as valproic acid, are ongoing in patients with tauopathy.

Another potential approach for modifying tau phosphorylation is through manipulation of tau glycosylation [91]. Certain serine and threonine residues of tau are post-translationally modified through the addition of �-N-acetylglucosamine (O-GlcNAc), and the levels of tau phosphorylation and O-GlcNAc are reciprocally regulated so that increased levels of tau OGlcNAc results in decreased phosphorylation. The cleavage of O-GlcNAc from tau is mediated by the enzyme O-GlcNAcase, and a recent study has shown that acute administration of an inhibitor of this enzyme, thiamet-G, to normal rats caused an apparent reduction of tau phosphorylation at ser396, thr231 and ser404 [92].

Tau Acetylation Inhibitors

In a recent study, a new mechanism regulating the turnover of pathogenic tau has been proposed [93]. The authors showed that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy and that tau acetylation prevents degradation of phosphorylated tau. Histone acetyltransferase p300 is involved in tau acetylation, and the class III protein deacetylase SIRT1 in deacetylation. Deleting SIRT1 enhanced levels of acetylated-tau and pathogenic forms of p-tau. Inhibiting p300 with a small molecule promoted tau deacetylation and eliminated p-tau associated with tauopathy. Thus modulating tau acetylation could be a new therapeutic strategy [93].

Tau Aggregation Inhibitors

Normal tau, which is largely unstructured in solution, can be induced to fibrillize in vitro in the presence of anionic co-factors such as heparin, fatty acid or RNA [94-96]. These anionic molecules have been proposed to facilitate tau–tau interaction by inducing conformational changes that result from electrostatic interactions with positively charged basic residues in the protein [97,98]. The conversion of soluble tau into oligomeric and fibrillar


species could result in tau gain of function and loss of function toxicities [69].

There is in vivo and in vitro experimental evidence suggesting a therapeutic benefit by the use of small molecoles acting as tau-aggregation inhibitors [99].

One of the first compounds identified that was able to block tau–tau interaction was the phenothiazine methylene blue [100].

Recent high-throughput screens yielded various potential drug candidates. Different classes of drugs, such as anthraquinones, N-phenylamines, phenylthiazolhydrazides, and rhodanines, can inhibit tau aggregation and, even more importantly, disassemble existing filaments [101-104]. Nevertheless, many of the existing tau assembly inhibitors have chemical or biological properties that will probably make them unsuitable for their use in vivo. It will be critical to identify compounds with good blood–brain barrier penetration, suitable half-lives and reasonable safety so as to allow for multi-month assessment in mouse tauopathy models. Another consideration is the dose of compound that will be required to interrupt multimerization in vivo, as many of the published tau fibrillization inhibitors require concentrations that are approximately equimolar to the amount of tau used in the assays [105].

Moreover, assuming that suitable tau fibrillization inhibitors can be identified, it will be important to understand how these molecules interrupt tau assembly. It is presently unclear whether mature tau fibrils or smaller tau multimers confer toxicity, as certain data support a role for the latter species [106].

Tau-Degradation Enhancers

Another promising therapeutic approach is to induce degradation of tau molecules that results in pathological conformations. There are two key-pathways by which cells can degrade misfolded cytosolic proteins. The first is the ubiquitin–proteosome system, in which proteins are modified with ubiquitin tags and subsequently degraded by the proteosome complex [107].

Oligomers or higher-order aggregates cannot enter the proteasome due to steric reasons, therefore are degraded through autophagy which requires encapsulation by an autophagosome and subsequent fusion with lysosome (autolysosome), where acidic lysosomal hydrolases degrade the contents of the vesicle [108,109].

Reports indicate the involvement of the ubiquitin–proteasome system (UPS) in the degradation of phosphorylated tau, as it has been shown that inhibitors of heat shock protein 90 (HSP90) can reduce the levels of highly phosphorylated tau [110,111] and improve behavioral endpoints in transgenic mice that express human mutant tau [112]. Moreover, other in vitro experiments showed that chaperones HSP90 and HSP70 promote tau solubility, enhance tau binding to microtubules, promote reduced tau-phosphorylation and thereby prevent tau aggregation [112,113].

While the chaperones HSP70 and HSP90 possess the ATPase function that ultimately leads to protection or destruction of a ligand, there are a number of accessory proteins termed co-+ chaperones that can alter both ATPase activities of these proteins as well as substrate interactions [114-117]. Thus, identifying co-chaperones that specifically affect protein subclasses could provide more specific drug targets with fewer adverse consequences [118].

Oligomers or higher-order aggregates cannot enter the proteasome due to steric properties, and undergo degradation by autophagy. Even in the absence of any other risk factors, deficiency in autophagy in the central nervous system has been shown to lead to the accumulation of protein aggregates and progressive neurodegeneration [119]. Since accumulation of misfolded proteins is a common feature in multiple human neurodegenerative diseases, activation of autophagy has been proposed as a strategy against

neurodegeneration [120,121]. Several reports suggested that the up-regulation of cellular autophagy can result in a clearance of misfolded protein aggregates including those composed of tau [122].

There is growing evidence that aggregated tau can be degraded by autophagy and that an upregulation of the autophagy–lysosomal system with drugs such as rapamycin might be a potential strategy for the treatment of tauopathies [123]. Recently, it was found that clearance of tau was slowed in human tau-expressing neuroblastoma cells that were treated with the lysosomotropic agents NH4Cl or chloroquine. Furthermore, addition of the autophagy inhibitor 3-methyladenine led to enhanced tau accumulation and aggregation [124].

However, the mechanisms that lead to the autophagy dysfunction are still not clear and little is known about mechanisms through which defects in autophagy might be involved in specific neurodegenerative diseases. Furthermore, as induction of autophagy is frequently associated with cell death, it remains a challenge to identify molecular targets whose inhibition can specifically activate autophagy without compromising cell viability [125].

PROGRANULIN-RELATED PHARMACOLOGICAL APP-ROACHES

In recent years, a giant step forward has been made by the identification of a second contributor in the pathogenesis of FTLD.

Progranulin (PGRN) is an evolutionarily conserved, secreted glycoprotein, widely expressed in different tissues [126], in neocortical neurons and in activated microglia [12,127]. The normal function of PGRN is complex and still not well understood, with the full-length form of the protein having trophic and anti-inflammatory activity, whereas proteolytic cleavage generates granulin peptides that promote inflammatory activity with an unclear role in neurodegeneration [128]. Progranulin mediates cell growth, and cell cycle progression, up to tumorogenesis if overexpressed [129,130]; its neurotrophic properties have also been demonstrated in neuronal cultures [131], suggesting a role for this protein in neuronal survival. Mutations in the gene encoding progranulin (granulin, GRN) are the most frequent cause of familial FTLD identified so far [12,13,132].

GRN mutations are loss of function mutations leading to severe PGRN haploinsufficiency, mostly due to out-of-frame insertions or deletions, splice site, or nonsense mutations that introduce a premature termination codon and result in the degradation of the mutant messenger RNA via nonsense-mediated decay [133-138].

Possible mechanisms whereby PGRN deficiency leads to neurodegeneration include long-term depletion of neurotrophic property and defective response to initial neuronal injury. Indeed, the mutations result in severe reduction of PGRN in tissue and biological fluids of patients and PGRN dosage in cerebrospinal fluid and plasma should be considered as a useful tool for GRN mutation screening [139-141] (see Fig. 2).

Given the haploinsufficiency mechanism, GRN is a particularly appealing gene for drug targeting and restoring PGRN levels by influencing its turnover or production is a promising therapeutic approach. One of the most promising results in that direction has been recently reached by Capell and colleagues [142]. They screened four compounds capable of inhibiting proteolytic degradation of PGRN, treating neuronal culture cells with different varieties of protease cell inhibitors. Subsequently cell lysates were analyzed for an increase in PGRN levels. Bafilomycin A1(BafA1),which is a member of the plecomacrolide sub-class, causes an increase in intracellular PGRN levels independently of lysosomal degradation and autophagy activation, suggesting a possible effect mediated early within the secretory pathway. The work strongly demonstrated that Bafa1 selectively inhibits the vacuolar ATP-ase


(v-ATPase), an enzyme preventing vesicular acidification in cellular system. Interestingly, other v-ATPase inhibitors, namely concanamycin A, archazolid B, and apicularen A [143] also increase intracellular and extracellular levels of PGRN.

Next step was to evaluate v-ATPase inhibitors and other alkalyzing agents in vivo, in the organotropic cortical slice cultures derived from GRN knock-out mice [144,145].

An increase in PGRN in the culture media was achieved with BafA1 and cloroquine, a drug frequently used as malaria prophylaxis and treatment of autoimmune disorders [146]. Also bepridil and amiodarone, used for the treatment of angina pectoris or arythmias, significantly increased PGRN levels in selective media. Interestingly, these findings were confirmed in a small sample of lymphoblastoid cells from healthy controls and FTLD-TDP patients carrying a GRN loss-of-function mutations. The long lasting effect suggested a translational upregulation of PGRN initiated by the intracellular pH changes induced by v-ATPase inhibitors or alkalizing drugs.

A phase II clinical trial on amiodarone use in GRN mutated patients is actually ongoing in Brescia, Italy [EudraCT 2011-004571-37].

Recently, Cenik and collegues, using a different approach, identified suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor as an enhancer of GRN expression [147]. In cultured cells, cotransfected with a luciferase-plasmid reporter, SAHA treatment dose dependently increased PGRN

mRNA and protein levels. Similar trichostatin A and structurallyunrelated M344 HDAC inhibitors increased GRN expression, suggesting a common therapeutic mechanism, recently implicated in other neurodegenerative conditions [148-151]. Theneuroprotective agent Resveratrol [152-155] even with a different unknown mechanism enhanced SAHA effect on PGRN expression [147]. Finally, SAHA was tested in fibroblasts from GRN mutated patients leading to a very promising restoring of near-normal GRN expression levels [147].

Since PGRN is a secreted protein, the understanding of its complex interaction and regulation is strictly linked to the identification and study of progranulin receptors.

A Genome-wide association study (GWAS) [156] aimed to find genetic variants associated with plasma progranulin levels, identified the gene sortilin (SORT1), coding for a vsp10-domain-containing receptor, known as neuronal growth factor receptor [157-161] SORT1 overexpression in cellular models significantly reduced extracellular PGRN, while SORT1 knockdown increased PGRN extracellular levels, supporting the hypothesis that SORT1 isa receptor of GRN [156].

Interestingly, the identification of sortilin as the major PGRN interactor has been independently confirmed using an unbiased binding screening [21].

In further investigation, PGRN colocalized and interacted directly with sortilin on the surface of neuronal cells. The same work showed that PGRN deficiency in a GRN+/- mouse model is

Fig. (2). FUS and TDP-43 proteinopathies. The figure summarize physiopathological models of TDP-43 and FUS-associated neurodegeneration. See text for a detailed explanation of current mechanisms implicated in these proteinopathies. Note that mRNA accumulation in C9orf72 mutations and prion-like domains are mechanism still under investigation.


fully normalized by deletion of SORT1 expression, clearly opening new therapeutic perspectives.

Finally, a recent study showed that progranulin was also a ligand for the tumor necrosis factor receptor (TNFR); their interaction leads to signaling modulation and inflammation in multiple arthritis mouse models [162].

Collectively, these results not only provide strong evidence for the role of progranulin in vivo, but also open new potential therapeutic targets for FTLD-TDP, highlighting the importance of both genetic and functional studies in the search for progranulin interactors.

TDP-43 AND FUS PROTEINOPATHIES: EMERGING ROLE OF FUTURE TARGETS

Pathological studies link GRN mutations to FTLD-TDP neuropathology, suggesting a possible role of PGRN as an upstream mediator of TDP-43 pathology [163,164]. Neurons lacking PGRN expression have significantly increased TDP-43 fragmentation and accumulation of insoluble TDP-43 [164] even if this finding was not confirmed in other studies [165].

As previously described, FTLD-TDP is the most frequent FTLD pathological subtype [166-168]. TDP-43 is a nuclear riboprotein [169], known as transcriptional splicing regulator [170-172]. Most of the reported pathogenic mutations within TARDBP gene in ALS and FTD patients are missense changes in exon 6, encoding the C-terminal, glycine–rich domain [173-175]. The pathogenetic mutations might lead to impaired nuclear import, altering exon skipping or transcriptional activity [176].

TDP-43 pathology is characterized by hyperphosphorylation, ubiquitination, and depletion of nuclear TDP-43, as well as cytoplasmic inclusions containing truncated TDP-43 [18,177]. This raises the question of whether loss of a nuclear function or gain of toxic cytoplasmic function could be the primary causes of TDP-43 pathology.

The spectrum of interactions of TDP-43 with RNA molecules, and not necessarily with splicing complexes, includes a multitude of neurodegeneration related transcripts, such as Sortilin, the PGRN receptor, and FUS [178-180].

The recent identification of TMEM106B, coding for an uncharacterized transmembrane protein, as FTLD-TDP risk factor needs further investigation in molecular biology, clarifing the relevance of these genetics and epidemiological findings [181-184].

The recent identification of pathogenic hexanucleotide repetition within C90RF72 gene in familial FTD-ALS linked to chromosome 9 opens new perspectives in FTLD understanding [185,186]. Preliminary findings suggested a toxic effect of this genetic alteration on RNA metabolism, probably leading to mRNA accumulation and toxicity [185,186]. That publications also suggested a high frequency of the same repeats in sporadic ALS and FTD cases, although in lower prevalence these repeats have been found in neurologically normal controls as well. In this perspective the next few months will be crucial for the identification and characterization of C90RF72 in FTLD spectrum.

FUS is a heterogeneous nuclear ribonucleoprotein (hnRNP), with low expression in cytoplasm and a conserved C-terminal region, strikingly similar to TDP-43. Mutations within FUS gene have been reported in ALS and

FTD familial forms, characterized by pathological cytoplasmatic aggregates of FUS with nuclear to cytoplasmatic translocation [187-189].

Importantly, TDP-43 positive inclusions are absent in FUSmutation carriers, implying that neurodegenerative processes driven by FUS mutations are independent of TDP-43 aggregation [188].

The common philological and structural characteristics of TDP-43 and FUS also reflect common physiological functions. The precise roles of TDP-43 and FUS are not fully elucidated but both are multifunctional proteins involved in gene expression regulation including transcription, RNA splicing, RNA transport and translation, micro RNA processing [172,190] and FUS may play a role in the maintenance of genome integrity.

TDP-43 and FUS shuttle between nucleus and cytosol, suggesting a possible role in modulating normal neuronal development, neuronal plasticity or other cellular properties by altering mRNA transport and local translation in neurons [191-194].

Interestingly, FUS and TDP-43 harbor also a “prion domain” very similar to the specific one present in prion proteins, leading to pathological misfolding transmissible between healthy cells or species [195-198]. Recent findings suggest a possible spreading of the disease along different brain regions with a prion like-mechanism [199-201]. In this case, positive therapeutic outcomes might need a supportive treatment able to prevent the spread of the disease [197].

The discovery of TDP-43 and FUS represent the beginning of a new paradigm in FTLD. Defining the normal roles of these ribonucleoproteins is essential to determine if mutants or abnormal aggregation lead to general or specific alterations of gene expression. Both cellular and animal models are now essential to define the link between TDP-43 and FUS and disease and to find possible specific targets for a future therapeutic target approach [202-204] (see Fig. 2).

TARGETING RARE CAUSES OF FTLD: THE CASE OFVCP AND CHMP2

VCP is a ubiquitously and highly expressed member of the type II AAA+ (ATPase associated with various activities) ATPase family. Rare missense mutations within VCP gene lead to a clinical phenotype characterized by Inclusion body myopathy, Paget’s disease and FTLD associated with TDP-43 pathology. VCP is essential during cell cycle progression to post-mitotic nuclear envelope reformation and Golgi reassembly, DNA damage repair and protein degradation via the ubiquitinproteasome system and endoplasmic reticulum associated protein degradation (ERAD) pathways. Recent findings suggest that VCP pathology shifts the degradation of substrates from ubiquitinproteasome system to autophagy [205,206]. Thus, autophagy and ubiquitin proteosome system will be promising targets for this complex disorder. On the other hand the link between VCP and sporadic TDP-43 proteinopathies should be clarified [207].

Mutation in the CHMP2B gene is a very rare cause of monogenic FTLD linked to chromosome 3, found only in a single Danish family. Neuropathology is characterized by neural inclusions not immunoreactive for FUS and by enlarged vacuoles considered aberrant late endosomes [208]. In the recommended nomenclature for neuropathologic subtypes of FTLD, these cases are classified as FTLD-UPS (although some cases of FTLD-UPS are negative for CHMP2B mutation) [209].

CHMP2B is part of the endosomal complex (ESCRTIII) [210]. ESCRT-III has a role in two protein degradation pathways that converge on the lysosome: the endosome-lysosome pathway and autophagy. Both these systems are functionally impaired by CHMP2B mutations. The endosomelysosome pathway is affected by an impaired fusion of endosomes with lysosomes [209,211], a mechanism shared also by other neurodegenerative diseases (Charcot-Marie-Tooth Type 2B) [212,213]. It is still not fully understood how these alterations lead to neurodegeneration, although different mechanisms involving growth factors and neurotransmitter receptors have been proposed [214,215]. Autophagy is a cellular system that degrades damaged organelles,


proteins and other cellular components. As a consequence of CHMP2B mutation, autophagosomes accumulates in neurons.

Even this mechanism is commonly present in other neurodegenerative diseases, like Alzheimer’s disease [216,217], Parkinson’s Disease [218,219] and prion disease [220,221], underlying the global relevance of these pathways for novel therapeutic strategies.

OTHER PHARMACOLOGICAL APPROACHES

Other classes of drugs have been tested for their potential role on selective anatomo-functional pathways primarily involved in FTLD.

From this perspective, methylphenidate acts on dopamine-related orbitofrontal connections with striatum, modulating risk-taking behaviours [222-224].

Also antiepileptic drugs (carbamazepine, topiramate, valproic acid) [225-227] may act as behavioral symptom modulators and as mood stabilizer.

Recent findings on neuropeptide oxitocin and its role in social cognition and emotional processing have represented the hypothetical base for a symptomatic approach in FTLD. In a recent clinical trial on 20 patients the effect of a single dose of intranasal oxitocine versus placebo was evaluated, showing a significant reduction of behavioral disturbances [228].

Table 2. Principal Candidate Molecules in Different Pathological Domains [See Text for Details]

Domains of pharmacoteraphy

Proposed mechanism Candidate molecules References

Neomycine 56 Shifting the tau isoform ratio from 4R to 3R

Mitoxantrone 57-58

\MAPT splicing modulators

Spliceosome-mediated RNA trans-splicing (SMarT) - 62-63

Reverse fast axonal transport deficits by functionally substituting tau Paclitaxel 71-72-73 Microtubule-stabilizing drugs Promotion of microtubule assembly NAPVSIPQ (Davunetide) 74-75-76

Lithium 86-87-88 Inhibition of selective kinases capable of phosphorylating tau (i.e. GSK-3� inhibitors)

Valproic acid 89-90

Tau phoshorilation inhibitors

Manipulation of tau glycosylation Thiamet-G 91-92

Tau Acetylation inhibitors

Promotion of tau deacetylation since tau acetylation prevents degradation of phosphorylated tau

- 93

Phenothiazine methylene blue 100

Anthraquinones 101

N-phenylamines 102

Phenylthiazolhydrazides 104

Tau aggregation inhibitors

Inhibition of the conversion of soluble tau into oligomeric and fibrillar species induced in the presence of anionic co-factors

Rhodanines 103

Chaperones HSP90 and HSP70 110-111-112-113 Promotion of the ubiquitin–proteasome system (UPS)

Co-chaperones 118

Rapamycin 123

Tau-degradation enhancers

Up-regulation of cellular autophagy resulting in a clearance of misfolded proteins

NH4Cl or chloroquine 124

Mitochondrial energy production

Reduction of neurotoxicity of mitochondrial complex I inhibitors Coenzyme Q10 (CoQ10) 232

Bafilomycin A1(BafA1) concanamycin A Archazolid Apicularen A

142 - 143

Cloroquine 142

Bepredil 142

Vacuolar - ATPase inhibition

Amiodarone 142

Suberoylanilide hydroxiamic acid (SAHA)

147

Trichostatin A, M344 147-148 -149-150-151- 152

Histone deacetylase inhibition

Resveratrol 147-152-153-154-155-

Progranulin - restoring

Modulation of Sortilin (progranulin receptor) expression - 156-157-158-159-160-161

Modulation of TDP-43 and/or FUS aggregation / expression - 191-192-193-194 TDP-43 and FUS proteinopathies Modulation of TDP-43 and/or FUS prion-domain - 197- 199-200-201

VCP pathology Autophagy and/or Ubiquitin proteosome system modulation - 205-206

CHMP2B mutation Autophagy modulation - 209-210-211


From this perspective, there is growing evidence about a key role of specific subcortical regions like hypothalamus in the modulation of the behavioral disturbances in FTLD, opening up to new therapeutic targets [229,230].

Considerable evidence has pointed to an impairment of mitochondrial energy production as a possible upstream event in the chain of pathological events leading to tau aggregation and neuronal cell death [231]. Since Coenzyme Q10 (CoQ10) is a physiological cofactor of mitochondrial respiratory chain, different research groups postulated a possible role for CoQ10 in the reduction of neurotoxicity of complex I inhibitors. A double blind, randomized, placebo controlled, clinical phase II study was conducted to study the short-term effects of oral CoQ10 treatment on brain energy metabolites and clinical disease severity in PSP patients. The study proved that a 6-week treatment was safe and tolerable and resulted in improvement of cerebral energy metabolism, especially in occipital lobes, and concomitantly in mild clinical improvement [232]. A long-term treatment is warranted and further studies to verify these results are needed. A phase III trial of coenzyme Q10 for 12 months in patients with PSP is currently ongoing (NCT00382824).

Another randomized, double-blind, placebo-controlled phase I pilot study, also targeting mitochondrial dysfunction, is under way to examine the safety and tolerability of a combination of pyruvate, niacinamide and creatine over six months in Progressive Supranuclear Palsy (PSP) patients (NCT00605930).

CONCLUSIONS

Recent discoveries have already laid the rational foundation for clinical studies in tauopathies, while for other proteinopathies much work has to be done to better define pathological mechanisms and thus, possible targets. A number of clinical trials are ongoing (see Tables 1 and 2 for details).

For the future, molecular research and trials should consider the pathology of neurodegeneration more than the single clinical entity. In this perspective, new biological markers might be the link between the understanding of pathological mechanisms and the potential disease modifying therapies.

DECLARATION OF COMPETING INTERESTS AND FINANCIAL DISCLOSURE

None of the Authors has any financial interest related to the publication of the present manuscript. Authors disclose all financial involvements connected with the work, as well as all sources of support, including government and industry support.

ABBREVIATIONS

AAA+ = ATPase associated with various activities ALS = Amyotrophic Lateral Sclerosis AMPA = alpha-amino-3-hydroxy-5-methyl-4- isoxazole

propionic acid bvFTD = Behavioral variant Frontotemporal Dementia CDK5 = Cell-cycle dependent kinase-5 CHMP2B = Charged multivesicular body protein 2B gene CoQ10 = Coenzyme Q10 ERAD = Endoplasmic reticulum associated protein

degradation ERK2 = Extracellular signal-related kinase 2 ESCRT-III = Endosomal sorting complex required for transport FTLD = Frontotemporal Lobar Degeneration

FTLD-FUS = FTLD with FUS-positive inclusions FTLD-TAU = FTLD with tau inclusions FTLD-TDP = FTLD with ubiquitin and TDP-43-positive

inclusions FTLD-UPS = FTLD with positive immunohistochemistry

against proteins of the ubiquitin proteasome system

FUS = Fused in sarcoma GRN = Granulin gene GSK-3 = Glycogen synthase kinase-3 GWAS = Genome-wide association study HDAC = Histone deacetylase hnRNP = Heterogeneous Ribonucleoprotein particle HSP90 = Heat shock protein 90 MAO = Monoamine oxidase inhibitors MAPT = Microtubule associated protein gene MARK = Microtubule affinity-regulating kinase NFT = Neurofibrillary tangles NMDA = N-methyl-D-aspartate NPI = Neuropsychiatric Inventory Scale O-GlcNAc = O-linked-N-acetylglucosamine PGRN = Progranulin PNFA = Progressive Non-fluent Aphasia PSP = Progressive Supranuclear Palsy SAHA = Suberoylanilide hydroxamic acid SD = Semantic Dementia SMarT = Spliceosome-mediated RNA trans-splicing SORT1 = Sortilin geneSSRI = Selective Serotonin Reuptake inhibitors TARDBP = TAR DNA-binding protein gene TDP43 = TAR DNA-binding protein 43 TMEM106B = Transmembrane protein 106B gene TNFR = Tumor Necrosis Factor receptor UPS = Ubiquitine Proteasome System VCP = Valosing Containing Protein gene

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Received: November 17, 2011 Revised: December 29, 2011 Accepted: January 01, 2012

disease-modifying therapies in frontotemporal lobar degeneration

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