Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS.

Familial amyotrophic lateral sclerosis (FALS) is caused, in 20% of cases, by mutations in the Cu/Zn superoxide dismutase gene (SOD1). Although motor neuron injury occurs through a toxic gain of function, the precise mechanism(s) remains unclear. Using an established NSC34 cellular model for SOD1-associated FALS, we investigated the effects of mutant SOD1 specifically in cells modelling the vulnerable cell population, the motor neurons, without contamination from non-neuronal cells present in CNS.

The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.

Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these conditions. We addressed whether this represents a posttranslational modification at cysteine residues by systematically mutating cysteine residues in human DJ-1.

Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease.

Dominant mutations in the gene for alpha-synuclein, a small presynaptic protein, can cause Parkinson's disease. Although there is still substantial debate about the precise mechanisms, alpha-synuclein is toxic to vulnerable neurons, probably as a result of its tendency to aggregate. Opposing this is another gene product that, when mutated, causes a recessive form of parkinsonism, parkin.

L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system.

Mutations in a gene on chromosome 1, DJ-1, have been reported recently to be associated with recessive, earlyonset Parkinson's disease. While one mutation is a large deletion that is predicted to produce an effective knockout of the gene, the second is a point mutation, L166P, whose precise effects on protein function are unclear. In the present study, we show that L166P destabilizes DJ-1 protein and promotes its degradation through the ubiquitin-proteasome system.

Microarray analysis reveals induction of heat shock proteins mRNAs by the torsion dystonia protein, TorsinA.

An in-frame deletion (Delta E302/303) in the TorsinA gene has been demonstrated to be responsible for primary torsion dystonia, showing dominant inheritance with reduced penetrance. The Delta E302/303 torsinA mutation forms intracellular ER derived inclusions in a variety of cultured cells, which may suggest that the mutations might evoke ER stress. We used microarray analysis of human derived cell lines expressing the Delta E302/303 torsinA mutation in order to reveal alterations in gene expression in the hope of identifying genetic modifying loci or novel markers for disease pathogenesis.

Co-ordinate transcriptional regulation of dopamine synthesis genes by alpha-synuclein in human neuroblastoma cell lines.

Abnormal accumulation of alpha-synuclein in Lewy bodies is a neuropathological hallmark of both sporadic and familial Parkinson's disease (PD). Although mutations in alpha-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic cell death occurs remains unknown. We investigated transcriptional changes in neuroblastoma cell lines transfected with either normal or mutant (A30P or A53T) alpha-synuclein using microarrays, with confirmation of selected genes by quantitative RT-PCR.