Mitophagy in neurodegenerative diseases

Abstract

Neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are a complex "family" of pathologies, characterised by the progressive loss of neurons and/or neuronal functions, leading to severe physical and cognitive inabilities in affected patients. These syndromes, despite differences in the causative events, the onset, and the progression of the disease, share as common features the presence of aggregate-prone neuro-toxic proteins, in the form of aggresomes and/or inclusion bodies, perturbing cellular homeostasis and neuronal function (Popovic et al., 2014), and the presence of dysfunctional mitochondria. The removal of protein aggregates and of damaged organelles, through the ubiquitin-proteasome system (UPS) and/or the autophagy/lysosome machinery, is a crucial step for the maintenance of neuronal homeostasis. Indeed, their impairment has been reported as associated with the development of these diseases. In this review, we focus on the role played by mitophagy, a specialised form of autophagy, in the onset and progression of major neurodegenerative diseases, as well as on possible therapeutic approaches involving mitophagy modulation.

TBK1 regulates autophagic clearance of soluble mutant huntingtin and inhibits aggregation/toxicity in different models of Huntington’s disease

“…Phosphorylation on OPTN or p62 was shown to facilitate the autophagy-dependent clearance of damaged/dysfunctional mitochondria (Matsumoto et al, 2015;Richter et al, 2016), a common defect in many neurodegenerative diseases (Rodolfo et al, 2018;Wang et al, 2019) and misfolded proteins and aggregates of proteins linked to neurodegenerative diseases, such as mutant SOD1 (Korac et al, 2013) and HTT (Matsumoto et al, 2011). TBK1-mediated enhancement of cargo/substrate recognition by the adaptors OPTN and p62, and OPTN mRNA levels were shown to be partially reduced in HD patient brain tissues (Hodges et al, 2006).…”

Vacuolar hydrolysis and efflux: current knowledge and unanswered questions

“…There, it recruits and activates PRKN, an E3 ubiquitin ligase, which then ubiquitinates several mitochondrial outer membrane proteins, targeting the damaged mitochondria for degradation via mitophagy [91,99]. Mutations in PINK1 and PRKN are associated with autosomal recessive familial Parkinson disease [100][101][102], underscoring the important role of mitophagy in clearing dysfunctional mitochondria.…”

Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis

“…Then, degradative autophagy process removal could lead to neuronal cell death and mortality [12]. Activated autophagy potentially omits neurodegenerative associated proteins such as mutant amyloid-β peptides, hyper phosphorylated tau proteins, amyloid precursor protein (APP), Lewy bodies components and α-synuclein, huntingtin, type 1 superoxide dismutase, Alsin Rho Guanine Nucleotide Exchange Factor 2, and optineurin [18][19][20][21]. The severity of the disease closely correlates with the content of impaired proteins [22].…”