tailieunhanh - Báo cáo khoa học: Emerging pathways in genetic Parkinson’s disease: Autosomal-recessive genes in Parkinson’s disease – a common pathway?

Rare, inherited mutations causing familial forms of Parkinson’s disease have provided insight into the molecular mechanisms that underlie the genetic and sporadic forms of this disease. Loss of protein function result-ing from autosomal-recessive mutations in PTEN-induced putative kinase 1 (PINK1), Parkin and DJ-1 has been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clear-ance and oxidative stress. | MINIREVIEW Emerging pathways in genetic Parkinson s disease Autosomal-recessive genes in Parkinson s disease -a common pathway Julia C. Fitzgerald and Helene Plun-Favreau Department of Molecular Neuroscience Institute of Neurology University College London UK Keywords cell death DJ-1 HtrA2 mitochondria mutation neuron Parkin Parkinson s disease PINK1 signalling Correspondence H. Plun-Favreau Department of Molecular Neuroscience Institute of Neurology University College London Queen Square London WC1N 3bG UK Fax 44 0207 278 5616 Tel 44 0207 837 3611 ext. 3936 E-mail Received 7 July 2008 revised 9 September 2008 accepted 15 September 2008 doi Rare inherited mutations causing familial forms of Parkinson s disease have provided insight into the molecular mechanisms that underlie the genetic and sporadic forms of this disease. Loss of protein function resulting from autosomal-recessive mutations in PTEN-induced putative kinase 1 PINK1 Parkin and DJ-1 has been linked to mitochondrial dysfunction accumulation of abnormal and misfolded proteins impaired protein clearance and oxidative stress. Accumulating evidence suggests that wild-type PINK1 Parkin and DJ-1 may be key components of neuroprotective signalling cascades that run in parallel interact via cross talk or converge in a common pathway. Parkinson s disease PD is a common neurode-generative disorder with no known cure estimated to affect 4 million people worldwide. The disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta and the presence of protein inclusions called Lewy bodies. The death of dopamine neurons in the substantia nigra pars com-pacta alters neurotransmitter balance in the striatum resulting in the progressive loss of movement control the principal hallmark of PD encompassing clinical features such as resting tremor bradykinesia postural instability and rigidity. The most common form of PD