Parkinson's disease

Abstract

Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity. Current medications only provide symptomatic relief and fail to halt the death of dopaminergic neurons. A major hurdle in development of neuroprotective therapies are due to limited understanding of disease processes leading to death of dopaminergic neurons. While the etiology of dopaminergic neuronal demise is elusive, a combination of genetic susceptibilities and environmental factors seems to play a critical role. The majority of PD cases are sporadic however, the discovery of genes linked to rare familial forms of disease (encoding alpha-synuclein, parkin, DJ-1, PINK-1 and LRRK2) and studies from experimental animal models has provided crucial insights into molecular mechanisms in disease pathogenesis and identified probable targets for therapeutic intervention. Recent findings implicate mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation as key molecular mechanisms compromising dopamine neuronal function and survival as the underlying cause of pathogenesis in both sporadic and familial PD. In this review we provide an overview of the most relevant findings made by the PD research community in the last year and discuss how these significant findings improved our understanding of events leading to nigrostriatal dopaminergic degeneration, and identification of potential cell survival pathways that could serve as targets for neuroprotective therapies in preventing this disabling neurological illness.

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

“…The epidemiological as well as animal studies suggest that environmental factors, genetic predispositions, and the interplay between the two factors are implicated in the PD 3 pathogenesis (1), although the underlying molecular mechanisms remain largely unknown. ␣-Synuclein is a major component of Lewy bodies (LB), the pathological hallmark of Parkinson disease (2).…”

“…Here, we present evidence that MMP3-mediated ␣-synuclein cleavage plays a pivotal role in the pathogenesis of PD. 1 Both authors should be regarded as joint first authors. 2 To whom correspondence should be addressed: 6900 Lake Nona Blvd., Orlando, FL 32827.…”

A reaction to mitochondria in action

“…Because of the cascading nature of the ETC assembly, it is generally believed that SO production is directly proportional to ATP production, such that both SO and ATP production are regulated (under physiological conditions) mainly by O 2 and energy substrate (e.g., glucose) availability. However, in pathological settings an aberrant sustained increase in SO production and a reduction in ATP production may occur as the result of impairment of complex 1, a scenario believed to happen in the dopamineproducing neurons that degenerate in Parkinson's disease [7]. But recent findings, bolstered by technological advances, challenge the concept that SO is normally produced in a graded manner proportional to ETC activity.…”

MicroRNAs in neurodegenerative disorders

“…Our knowledge regarding the molecular mechanisms of neurodegeneration has improved substantially in the last two decades, prompted by the discovery of the genes responsible for the familial forms of these disorders. 2 An emerging theme from a large body of cellular and in vivo investigations suggests that the amount of the disease associated protein, or of the particular pathogenic isoform, appears critical in promoting its aggregation and likely toxicity. Recent studies have demonstrated that certain miRNAs are differentially expressed in the human brain and regulate the expression of genes implicated in specific neurodegenerative diseases ( Table 1).…”