Mitochondrial Pathobiology in Parkinson's Disease and Amyotrophic Lateral Sclerosis

Abstract

Abstract. Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are the second and third most common human adult-onset neurodegenerative diseases, respectively, after Alzheimer's disease. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of PD and ALS are inherited, and genes causing these diseases have been identified. Morphological, biochemical, and genetic, as well as cell and animal model, studies reveal that mitochondria could have a role in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review will present how mitochondrial pathobiology might contribute to neurodegeneration in PD and ALS and could serve as a target for drug therapy.

The Role of Mitochondrial Non-Enzymatic Protein Acylation in Ageing

“…This hypothesis is based on several well established observations in the literature: (1) Dysregulation of mitochondrial homeostasis has been implicated in ageing and a number of age-related diseases [12,64,65]. (2) A number of large scale proteomic studies have shown that mitochondrial proteins are highly acylated [29,43,66–68].…”

Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases

“…Mitochondrial dysfunction and oxidative stress are well-documented in PD; in particular, mitochondria in complex I have been found to be defective in both familial and sporadic PD (Lin and Beal, 2006; Matsuda et al, 2010; Martin, 2006, 2010; Chu and Zhe, 2010; Cookson, 2010; Morais et al, 2009; Lin et al 2009). With the focus on abnormal mitochondrial dynamics, little research attention has been paid to elucidating the involvement of Drp1 and mitochondrial fission and fusion imbalance in PTEN induced putative kinase 1 (PINK1) and parkin mutants of fruitflies and mouse models.…”

“…In ALS, mitochondrial abnormalities have been extensively described in both familial and sporadic ALS patients and also in transgenic mouse models generated with mutant SOD1 (Magrane and Manfredi 2009 2010; Zhou et al 2009, Kawamata et al 2008, Cassina et al 2008, Ilieva et al 2007, Martin 2006, 2009, 2010, Martin et al 2009, Raimondi et al 2006, Krasnianski et al 2005, Kirkinezos et al 2005, Zhu et al 2002, Dhaliwal and Grewal 2000). Histopathological research revealed that mitochondria may be targets of toxicity in ALS since vacuolated and dilated mitochondria with disorganized cristae and membranes in motor neurons have been observed in patients with ALS (Reddy and Reddy, 2010), and mitochondrial defects (e.g., impaired respiration and increased uncoupling proteins) have been reported in the spinal cords and muscle biopsies of patients with ALS.…”

Protection effect of piperine and piperlonguminine from Piper longum L. alkaloids against rotenone-induced neuronal injury

“…The opening of mitochondrial permeability transition pore (mPTP) is central to mitochondrial structure and function, including reactive oxygen species (ROS) production. A mutation in the mitochondrial gene PTEN-induced kinase 1 leads to selective opening of the mPTP (Gautier et al, 2012), and the pharmacological agent rasagiline, which is prescribed to PD patients, exerts its effect in part through the mPTP (Youdim et al, 2005), indicating that changes in mPTP opening can be a causal factor in PD (Martin, 2010;Mashayekhi et al, 2014). These findings also suggest that the mPTP could serve as a viable drug target (Penna et al, 2013;Rao et al, 2013).…”