Abstract
The mitochondrial ATP synthase is responsible for the production of cellular ATP, and it does so by harnessing the membrane potential of the mitochondria that is produced by the sequential oxidation of select cellular metabolites. Since the structural features of ATP synthase were first resolved nearly three decades ago, significant progress has been made in understanding its role in health and disease. Mitochondrial dysfunction is common to neurodegeneration, with elevated oxidative stress a hallmark of this dysfunction. The patterns of this oxidative stress, including molecular targets and the form of oxidative modification, can vary widely. In this mini review we discuss the oxidative modifications of ATP synthase that have been observed in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Oxidative modifications of ATP synthase in Alzheimer’s disease are well-documented, and there is a growing body of knowledge on the subject in Parkinson’s disease. The consideration of ATP synthase as a pharmacological target in a variety of diseases underlines the importance of understanding these modifications, both as a potential target, and also as inhibitors of any pharmacological intervention.
Highlights
Neurodegenerative DiseasesNeurodegeneration is the process of progressive atrophy and loss of functional neurons in the central nervous system, and in particular the brain
There are many genetic risk factors for Parkinson’s disease (PD), such as mutations to the SNCA gene that lead to the formation of α-synuclein aggregates known as Lewy bodies (Schulz-Schaeffer, 2010; Mahul-Mellier et al, 2020), as well as mutations to the PINK1 and parkin genes that lead to failed mitophagy, neuronal defects and even apoptosis (Goldberg et al, 2003; Palacino et al, 2004; WoodKaczmar et al, 2008)
ATP synthase was identified as HNE modified when the inferior parietal lobule (IPL) of Alzheimer’s disease (AD) patients were studied, and this was again coupled with the observation that ATP synthase catalytic activity was reduced (Perluigi, 2009)
Summary
Neurodegeneration is the process of progressive atrophy and loss of functional neurons in the central nervous system, and in particular the brain. The neurodegenerative process is not uniform, distinctions between which brain regions undergo atrophy, and by what molecular mechanisms the atrophy can be characterised, lead to the different neurodegenerative diseases that we recognise (Damier et al, 1999; Sabuncu, 2011; Dugger and Dickson, 2017). As global population demographics shift towards older ages, the prevalence of the disease will increase, creating a huge health and social care as well as an economic burden (Castro et al, 2010; Marasco, 2020). The pathophysiology of AD is best characterised by three main characteristics: the aggregation of the amyloid beta (Aβ) protein into plaques (Selkoe and Hardy, 2016; Makin, 2018), the formation of neurofibrillary tangles by the tau protein (Braak and Braak, 1991; Gao et al, 2018), and the dysfunction of mitochondria (Moreira et al, 2006; Swerdlow, 2018), the cell’s bioenergetic and signalling hubs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
