From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation

Abstract

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a neurodegenerative disorder caused by a polyglutamine expansion in the ATXN3 gene. In spite of the identification of a clear monogenic cause 25 years ago, the pathological process still puzzles researchers, impairing prospects for an effective therapy. Here, we propose the disruption of protein homeostasis as the hub of SCA3 pathogenesis, being the molecular mechanisms and cellular pathways that are deregulated in SCA3 downstream consequences of the misfolding and aggregation of ATXN3. Moreover, we attempt to provide a realistic perspective on how the translational/clinical research in SCA3 should evolve. This was based on molecular findings, clinical and epidemiological characteristics, studies of proposed treatments in other conditions, and how that information is essential for their (re-)application in SCA3. This review thus aims i) to critically evaluate the current state of research on SCA3, from fundamental to translational and clinical perspectives; ii) to bring up the current key questions that remain unanswered in this disorder; and iii) to provide a frame on how those answers should be pursued.

Keywords: Ataxin-3; Machado-Joseph disease; Molecular pathogenesis; Neurodegeneration; Spinocerebellar ataxia type 3; Therapeutic advances.

Fig. 1

Overview of the molecular pathogenesis of SCA3. An expansion of CAG repeats (above 60) in exon 10 of the ATXN3 gene is the underlying cause of SCA3. The translated protein therefore harbors an expanded polyglutamine stretch, between 2 UIMs. This expansion leads to misfolding of ATXN3, consequent oligomerization and accumulation of the abnormal protein in amorphous aggregates or amyloid fibers, which can be visualized as intracellular inclusions by immunohistochemistry. These changes consequently affect protein homeostasis, through a probable loss of deubiquitylase activity, impact in aggresomes, autophagy, the ERAD, and the proteasome. The loss of proteostasis has several consequences in cellular physiology, impacting the nucleus (namely misfolding of nuclear proteins, DNA damage, and changes in transcription), the mitochondria (through abnormal interaction with several mitochondrial proteins, stress of misfolded proteins, as well as a decrease in mitochondrial DNA), the ER (through the ERAD and induction of intracellular Ca²⁺ release), and cellular communication (through potential impairment of axonal transport and synaptic vesicle release). ATXN3 = ataxin-3; ER = endoplasmic reticulum; ERAD = endoplasmic reticulum–associated protein degradation; NES = nuclear export signal; NLS = nuclear localization sequence; TF = transcription factors; Ub = ubiquitin; UIM = ubiquitin-interacting motives

Fig. 2

Pipeline for therapeutic advances in SCA3. Based on the molecular pathogenesis of SCA3, several drugs that target various aspects of dysfunction have been tested in preclinical models of the disease. Drugs with promising preclinical trial results should be evaluated for their potential translation, namely to be acutely safe, chronically tolerated, have long-term efficacy without loss of effects, and be accompanied by drug-specific biomarkers and measures of drug target engagement. These are the drugs that should reach clinical trials first; if a drug is repurposable, a regulatory fast track can be used to reach the clinical trials more easily. Clinical studies in SCA3 also hold some particularities that are essential for their planning and design. Novel drugs or interventions that reach the clinical setting have to be integrated in the patient hub, which also includes symptom-directed treatments (pharmacological and nonpharmacological) and the patient associations and support groups. ASO = antisense oligonucleotide; ICARS = International Cooperative Ataxia Rating Scale; polyQ = polyglutamine; SARA = scale for the assessment and rating of ataxia; SCA = spinocerebellar ataxia