Mutations in cell death pathways, such as apoptosis, mitophagy, necroptosis, and autophagy, contribute to neuronal cell death and the progression of neurodegenerative diseases. Aberrant pro- and anti-apoptotic signaling, mitochondrial dysfunction, mis-regulation of autophagy or the unfolded protein response, and activation of the necrosome by stress and/or inflammation highlight just a few of the mechanisms by which neurons die or become diseased. Although many of these pathways are understood in non-neuronal cells, their mechanism of activation and dysregulation remains a mystery in neurons which present their own challenges.
PARP typically functions as a key player in the DNA repair pathway in response to oxidative stress. When cleaved by caspase 3 between Asp214 and Gly215, the N-terminal cleaved fragment inhibits DNA repair enzymes to push neurons toward apoptosis, making it a hallmark of apoptotic cells.
PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine protein kinase that protects cells from stress-induced mitochondrial dysfunction. It accumulates on the outer membrane of severely damaged mitochondria and recruits PARKIN to induce degradation through autophagy. PINK1 mutations are linked with autosomal recessive early onset Parkinson’s disease.
Sequestosome 1 (SQSTM1, p62) is an autophagosome cargo protein that binds to protein aggregates to target them for selective autophagy. SQSTM1/p62 mutations lead to an increase in intracellular aggregation of α-synuclein, Huntingtin, Tau protein, and beta-amyloid to drive progression of Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease, respectively.
LC3A/B plays a critical role in autophagosome biogenesis and maturation and also functions as an adaptor protein to selectively recruit cargo to the autophagosome. An increase in LC3-positive microglia have been observed in tissues in Alzheimer’s disease patients with TREM2 mutations, suggesting that disruptions in TREM2-dependent autophagy can contribute to Alzheimer’s disease etiology.
Human Phospho-RIP3 (Ser227) phosphorylates MLKL1 to trigger TNF-induced necroptosis. This form of programmed cell death has been reported in multiple sclerosis and amyotrophic lateral sclerosis.