[Frontier researches for the development of molecular-targeted therapies for familial Parkinson disease].
Parkinson disease (PD), is a movement disorder pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the inherited forms of PD account for only 5 to 10% of PD cases, the identification of gene mutations in the genes implicated in familial PD in the past 10 years, including the findings regarding the a-synuclein, Parkin, ubiquitin-C-terminal hydrolase-L1 (UCH-L1), PINK1, DJ-1 and the ATP13A2 genes, has advanced understanding of the molecular mechanisms in each case of genetic PD. Most familial forms of PD develop at an early onset. However, recent identification of the leucine-rich repeat kinase (LRRK) 2 gene for a late-onset PD, the clinicopathological feature of which closely resembles that of sporadic PD, is expected to enable the clarification of the underlying causes of general PD. Recent studies on the physiological and pathological functions of these identified gene products have revealed overlapping pathogenetic pathways. The common features of these aberrant pathways are impaired protein degradation/quality control, mitochondrial dysfunction, and altered vesicle transport. Several attempts have been made towards developing molecular-targeted therapies directed against mitochondria (e.g., antioxidants, permeability transition pore modulators, and mitochondrial biogenesis stimulators), protein quality control and vesicle transport (e.g., gene silencing, immunization of asynuclein, and protofibril-destabilizing reagents). To ensure the successful implementation of such strategies, it is important to understand the events occuring at an early stage of PD. Further, studies using mammalian PD models for pharmacological analysis combined with studies employing lower organisms for genetic analyses such as worm, fly, and yeast will be helpful to determine effective prevention and treatment strategies for PD, which will replace the conventional symptomatic treatments for PD.
Imai
Yuzuru
Y
Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Takahashi
Ryosuke
R
D000818:Animals; D018390:Gene Targeting; D015316:Genetic Therapy; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008928:Mitochondria / Q000235:genetics; D024101:Mitochondrial Proteins; D015513:Oncogene Proteins; D018384:Oxidative Stress; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000628:therapy*; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012697:Serine Endopeptidases; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase
D000074923:High-Temperature Requirement A Serine Peptidase 2; D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D024101:Mitochondrial Proteins; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012697:Serine Endopeptidases; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C482860:UCHL1 protein, human; C111567:parkin protein; C495280:LRRK2 protein, human; C105131:PARK7 protein, human