The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.

Expanding insights of mitochondrial dysfunction in Parkinson's disease

PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson’s Disease

Parkinson disease is a complex, multifactorial neurodegenerative disease. Although a heritable basis was originally thought unlikely, recent studies have implicated several genes in its pathogenesis, and molecular findings now allow accurate diagnosis and challenge past criteria for defining Parkinson disease. Most importantly, genetic insights provide the rationale for new strategies for prevention or therapy, and have led to animal models of disease in which these strategies can be tested. Neuroprotective therapies can now be designed to slow or halt disease progression in affected subjects and asymptomatic carriers.

Genetics of Parkinson disease: paradigm shifts and future prospects.

Parkinson disease (PD) is a relatively common disorder of the nervous system that afflicts patients later in life with tremor, slowness of movement, gait instability, and rigidity Treatment of these cardinal features of the disease is a success story of modern science and medicine, as a great deal of disability can be alleviated through the pharmacological correction of brain dopamine deficiency Unfortunately these therapies only provide temporary, though significant, relief from early symptoms and do not halt disease progression In addition, pathological changes outside of the motor system leading to cognitive, autonomic, and psychiatric symptoms are not sufficiently treated by current therapies Much as the discovery of dopamine deficiency led to powerful treatments for motor symptoms, recent discoveries concerning the role of specific genes in PD pathology will lead to the next revolution in disease therapy Understanding why and how susceptible cells in motor and nonmotor regions of the brain die in PD is the first step toward preventing this cell death and curing or slowing the disease In this review we discuss recent discoveries in the fields of diagnosis and treatment of PD and focus on how a better understanding of disease mechanisms gained through the study of monogenetic forms of PD has provided novel therapeutic targets

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Diagnosis and treatment of Parkinson disease: molecules to medicine

Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the a...

What Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease

Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson9s disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-α treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.

https://www.jneurosci.org/content/jneuro/25/35/7968.full.pdf

Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death.

http://www.jbc.org/content/281/24/16193.full.pdf

Seong Who Kim

Papers

Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death.

Identification of far upstream element-binding protein-1 as an authentic parkin substrate

Recent advances in our understanding of Parkinson's disease