Abstract
Parkinson's disease (PD), clinically characterized by motor and nonmotor symptoms, is a common progressive and multisystem neurodegenerative disorder, which is caused by both genetic and environmental risk factors. The main pathological features of PD are the loss of dopaminergic (DA) neurons and the accumulation of alpha-synuclein (α-syn) in the residual DA neurons in the substantia nigra pars compacta (SNpc). In recent years, substantial progress has been made in discovering the genetic factors of PD. In particular, a total of 19 PD-causing genes have been unraveled, among which some members have been regarded to be related to mitochondrial dysfunction. Mitochondria are key regulators of cellular metabolic activity and are critical for many important cellular processes including energy metabolism and even cell death. Their normal function is basically maintained by the mitochondrial quality control (MQC) mechanism. Accordingly, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a kind of neurotoxin, exerts its neurotoxic effects at least partially by producing its toxic metabolite, namely, 1-methyl-4-phenylpyridine (MPP+), which in turn causes mitochondrial dysfunction by inhibiting complex I and mimicking the key features of PD pathogenesis. This review focused on three main aspects of the MQC signaling pathways, that is, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy; hence, it demonstrates in detail how genetic and environmental factors result in PD pathogenesis by interfering with MQC pathways, thereby hopefully contributing to the discovery of novel potential therapeutic targets for PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD), from which over 1% of the population older than 60 years of age worldwide has suffered from related serious and even fatal illness [1]
We mainly focused on mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy in order to gain a better understanding of the latest advances in mitochondrial quality control in PD pathogenesis, based on both genetic and environmental risk factors
Quite a few studies have shown that α-syn binds to the PGC-1α promoter under oxidative stress and leads to PGC-1α suppression, for which mitochondrial biogenesis is in turn compromised [45]
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD), from which over 1% of the population older than 60 years of age worldwide has suffered from related serious and even fatal illness [1]. Motor symptoms mainly include muscle rigidity, bradykinesia, posture disorders, and resting tremors. These symptoms are traditionally considered to largely result from the loss of DA neurons in the SNpc [3]. PD pathogenesis remains elusive, multiple essential processes have been found to contribute to the higher incidence among patients, including protein aggregation, impairment of the ubiquitin-proteasome pathway, oxidative stress, mitochondrial dysfunction, and neuroinflammation [9]. The neurotoxicity of MPTP is derived from its toxic metabolite 1-methyl-4-phenylpyridine (MPP+), which has a suppressive capacity over the electron transport chain by inhibiting the accumulation of complex I in the mitochondria, leading to mitochondrial dysfunction [15, 16]. We mainly focused on mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy in order to gain a better understanding of the latest advances in mitochondrial quality control in PD pathogenesis, based on both genetic and environmental risk factors (see Figure 1)
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