The Cell and Molecular Biology of Neurodegenerative Diseases: An Overview

Abstract

In this research topic, the primary focus is on understanding the cellular and molecular mechanisms in the pathogenesis of differ-ent neurodegenerative disorders. These include Alzheimer's dis-ease (AD), Parkinson's disease (PD), and polyglutamine (polyQ) expansion diseases. To date, no cure exists for these disorders and it is paramount that research efforts continue to focus on understanding the molecular underpinnings behind these disor-ders. This will enable better symptom-directed therapeutics and perhaps even curative treatments to be developed. Throughout this topic, it becomes evident that there are com-mon cellular pathways that are altered in these disorders, including protein, mitochondrial, and transcriptional homeostasis. In the case of AD, it has become widely accepted that AD is a synaptopa-thy, meaning that there is a loss or damage of synapses. This dam-age to synapses leads to altered neuronal circuitry. The neuron-specific, post-synaptic protein, Arc, has gained recent attention for its contribution in the regulation of memory consolidation. Ker-rigan and Randall (1) discuss how alterations of Arc protein in the brains of AD patients and animal models of AD may be a clue as to how synaptic transmission is altered in AD, and how this cellular pathway may be of interest for therapeutic development. The next three reviews discuss the molecular events underlying PD and how the normal function of specific proteins associated with PD can help shed light on the causes of familial and sporadic PD. Lim and Zhang (2) outline a range of studies that implicate aberrations in mitochondrial function and protein homeostasis, with oxidative stress as the possible link between these two. A review from Dr. Edward A. Fon's group complements this dis-cussion by focusing on the structure and function of Parkin, PINK1, and DJ-1 as they relate to PD (3). The second review from Dr. Fon's group digs even deeper into the role of Parkin and PINK1 in mitophagy in neurons. They discuss the importance of research initiatives to better define the roles of these two proteins in mitophagy and, in particular, within the context of a neuronal setting (4). The next five reviews focus on polyQ expansion diseases. Almeida et al. (5) provide a structural and functional view of trinu-cleotide repeats and encoded homopeptide expansions, emphasiz-ing polyQ expansions and their role in inducing the self-assembly, aggregation, and functional alterations of the protein, leading to neuronal toxicity and cell death. These authors focus on ataxin-3 and huntingtin (Htt), the main protein implicated in Machado– Joseph Disease (MJD) and Huntington's disease (HD) respectively. Drs. Durcan and Fon, also focus on ataxin-3 and its function as a deubiquitinating enzyme (6). These authors have recently identified ataxin-3's E3 ubiquitin ligase partners to be parkin and CHIP. As MJD patients often present with PD symptoms, the fact that parkin's activity is regulated by ataxin-3-mediated deubiquitination is a critical link for this phenotype. As mutant, but not wild-type ataxin-3 promotes clearance of parkin via the autophagy pathway, there seems to be a possibility that increased turnover of parkin contributes to pathogenesis in MJD. More-over, ataxin-3 also induces a reduction in CHIP levels. In light of these findings, the authors discuss the implications for the role of mutant ataxin-3's effect upon Parkin and CHIP levels in under-standing the molecular processes involved in SCA3 and perhaps other neurodegenerative disorders. Moumné et al. (7) discuss the role of transcriptional disruption in HD, specifically, as it relates to the transcriptional repressor, R element-1 silencing transcription factor (REST). REST is a transcriptional repressor of neuronal survival factors and nor-mally associates with wild-type Htt. However, there is an aberrant alteration of cytoplasmic retention of the transcriptional repres-sor REST by mutant Htt. The authors go on to describe studies that have implicated this aberrant effect of mutant Htt on REST function to regulate neuronal genes and how this may impact pathogenesis in HD. Du et al. (8) focus on depression, the major psychiatric manifestation of HD. They discuss potential mecha-nisms of pathogenesis identified from animal models and com-pare depression in HD patients with non-HD persons, asking the question; Does HD-related depression differ from non-HD persons? They also go on to discuss some molecular and cellular mechanisms which may contribute to depression in HD. Beitel et al. (9) discuss spinal and bulbar muscular atrophy (SBMA), a polyQ expansion disease caused by the expansion of a CAG tract in the androgen receptor (AR) gene. This review summarizes all of the aspects of AR metabolism, from posttrans-lational modifications, to protein degradation and transcriptional function that have been implicated in SBMA pathogenesis. Spencer et al. (10) offer a commentary on Western Pacific Amy-otrophic lateral sclerosis (ALS) – parkinsonism-dementia complex (PDC) that plagues the island populations of Chamorros on Guam, Japanese in Honshu Island's Kii Peninsula, and Papuan New Guineans in Irian Jaya, Indonesia. It is a spectrum disorder believed to be to be triggered by a toxin in the seed of the neuro-toxic cycad plant. This toxin is thought to induce a prototypical www.frontiersin.org