05-882 Sigma-AldrichAnti-Parkin Antibody, clone PRK8

Cardiomyocyte hypertrophy has been associated with diminished mitochondrial metabolism. Mitochondria are crucial organelles for the production of ATP, and their morphology and function are regulated by the dynamic processes of fusion and fission. The relationship between mitochondrial dynamics and cardiomyocyte hypertrophy is still poorly understood. Here, we show that treatment of cultured neonatal rat cardiomyocytes with the hypertrophic agonist norepinephrine promotes mitochondrial fission (characterized by a decrease in mitochondrial mean volume and an increase in the relative number of mitochondria per cell) and a decrease in mitochondrial function. We demonstrate that norepinephrine acts through α1-adrenergic receptors to increase cytoplasmic Ca(2+), activating calcineurin and promoting migration of the fission protein Drp1 (encoded by Dnml1) to mitochondria. Dominant-negative Drp1 (K38A) not only prevented mitochondrial fission, it also blocked hypertrophic growth of cardiomyocytes in response to norepinephrine. Remarkably, an antisense adenovirus against the fusion protein Mfn2 (AsMfn2) was sufficient to increase mitochondrial fission and stimulate a hypertrophic response without agonist treatment. Collectively, these results demonstrate the importance of mitochondrial dynamics in the development of cardiomyocyte hypertrophy and metabolic remodeling.

CONTEXT: The cause and pathogenesis of Parkinson's disease remain unknown; mitochondrial dysfunction, oxidative damage, environmental factors, and genetic predisposition might all be involved. Identification of the causative genes for familial Parkinson's diseases allow study of the pathogenesis of the disease at the molecular level. STARTING POINT: Katja Hedrich and colleagues studied 75 Serbian patients with early-onset Parkinson's disease for DJ-1 mutations (Neurology 2004; 62: 389-94). One patient was a compound heterozygote and another had a heterozygous exon deletion. DJ-1 mutations seem to be rare in this European population. By contrast, parkin mutations have been found in about 50% of familial cases and in 10-20% of cases without a positive family history. WHERE NEXT: The fact that parkin is a ubiquitin ligase gives special meaning to the molecular mechanism of neurodegeneration in general. In Parkinson's disease, Lewy bodies are immunoreactive for ubiquitin. Accumulation of abnormal proteins has also been seen in other neurodegenerative disorders. Disturbance of protein degradation by the ubiquitin-proteasome system might have a critical role in neurodegeneration. Although alpha-synuclein mutations are infrequent, alpha-synuclein accumulates in Lewy bodies, and alpha-synuclein fibrils impair the 26S proteasome function. UCH-L1 is also an abundant deubiquitylating enzyme, and its mutation is linked to PARK5. Furthermore, DJ-1 might interact with SUMO-1 (small ubiquitin-like modifier), which can counteract ubiquitin and stabilise proteins against degradation by the 26S proteasome. Uncovering the mechanisms of protein degradation should add importantly to understanding the neurodegenerative process in these neurodegenerative diseases.

The ubiquitin-proteasome system (UPS) is important for intracellular proteolysis, and is responsible for a diverse array of biologically important cellular processes, such as cell-cycle progression, signaling cascades and developmental programs. This system is also involved in the protein quality control, which maintains the health of the cell. Thus, the UPS provides a clue for understanding of the molecular mechanisms underlying various neurodegenerative diseases. In the last decade, we witnessed a tremendous progress in uncovering the mechanisms of Parkinson's disease (PD). Of the several genes that can cause familial PD, parkin, the causative gene of autosomal recessive juvenile parkinsonism (ARJP), is of a special interest because it encodes an ubiquitin-protein ligase, which covalently attaches ubiquitin to target proteins, designating them for destruction by the proteasome. This review summarizes recent studies on the UPS pathway with a special reference to parkin, focusing on how parkin is linked to the pathogenesis of ARJP.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. The major motor disabilities of PD are associated with the extensive loss of dopaminergic neurons in the substantia nigra pars compacta. The physiological changes and biochemical pathways involved in the selective demise of these neurons are still unclear. Recent studies have demonstrated that alterations or reductions in ubiquitin-mediated proteasome function can be causal of at least some forms of parkinsonism, and multiple lines of evidence suggest that this mechanism of protein degradation may play an important role in the etiology of PD.

Kindreds with Mendelian inheritance of Parkinson disease (PD) have been known since a long time ago. Nine loci have been mapped in familial PD by linkage study and four causative genes have been cloned. This paper discusses Park 1 and Park 2, the identification of which has brought about many advances in the studies on pathomechanism of PD. Investigations of these genes in familial PD have expanded their clinical and pathological phenotypes. However, to clarify the effect of mutations on these phenotypes, additional post-mortem neuropathological studies are required.

Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause alpha-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of alpha-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and alpha-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.