Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics

Abstract

Machado–Joseph disease (MJD) or spinocerebellar ataxia 3 (SCA3) is a rare, inherited, monogenic, neurodegenerative disease, and the most common SCA worldwide. MJD/SCA3 causative mutation is an abnormal expansion of the triplet CAG at exon 10 within the ATXN3 gene. The gene encodes for ataxin-3, which is a deubiquitinating protein that is also involved in transcriptional regulation. In normal conditions, the ataxin-3 protein polyglutamine stretch has between 13 and 49 glutamines. However, in MJD/SCA3 patients, the size of the stretch increases from 55 to 87, contributing to abnormal protein conformation, insolubility, and aggregation. The formation of aggregates, which is a hallmark of MJD/SCA3, compromises different cell pathways, leading to an impairment of cell clearance mechanisms, such as autophagy. MJD/SCA3 patients display several signals and symptoms in which the most prominent is ataxia. Neuropathologically, the regions most affected are the cerebellum and the pons. Currently, there are no disease-modifying therapies, and patients rely only on supportive and symptomatic treatments. Due to these facts, there is a huge research effort to develop therapeutic strategies for this incurable disease. This review aims to bring together current state-of-the-art strategies regarding the autophagy pathway in MJD/SCA3, focusing on evidence for its impairment in the disease context and, importantly, its targeting for the development of pharmacological and gene-based therapies.

Oxidative Stress in Spinocerebellar Ataxia Type 3 and Its Attenuation by Herbal Remedies in Traditional Chinese Medicine: A Systematic Review

“…The failure of accumulated modified proteins to be destroyed in UPS triggers a vicious cycle of ROS formation, mtDNA damage, and mitochondrial dysfunction. The TCM formulation that regulates autophagy through the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of the rapamycin kinase (mTOR) pathway, beclin-1/BCL2 complex, 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK)/unc-51-like autophagy activating kinase (ULK)/mTOR pathway, transcription factor EB ( TFEB ), and PTEN-induced kinase 1 (PINK1)/parkin pathway [ 88 ] has gained increasing popularity in the drug discovery field. Taken together, the degradation of mATXN3 through autophagy and stimulation of the antioxidant defense system contributing to neuroprotective effects can be targeted for the advancements in therapeutic interventions of TCM for SCA3.…”

Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances

“…Clinical symptoms showed improvements or were delayed in most patients; patients with younger age of onset, shorter disease duration, and lower Scale for the Assessment and Rating of Ataxia (SARA) scores displayed better responses to trehalose ( Noorasyikin et al, 2020 ). Other pharmacological inducers, such as lithium, temsirolimus, cordycepin, carbamazepine, and n-butylidenephthalide, were reported to enhance autophagy in preclinical studies related to SCA1, SCA2, and SCA3, with cellular or animal models exhibiting decreased levels of mutant proteins, reduced number of aggregates, and improved neuropathology ( Paulino and Nóbrega, 2023 ). Autophagy is currently one of the most studied targets in neurodegenerative diseases.…”

Disrupted cerebellar structural connectome in spinocerebellar ataxia type 3 and its association with transcriptional profiles

“…SCA3 is one of the most frequent polyQ diseases characterized by the formation of protein aggregates in neurons 20 . Pathological aggregates can affect other proteins and cellular components, progressively leading to the dysregulation and impairment of several cellular mechanisms 21,22 .…”