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First published online May 14, 2007
doi: 10.1242/10.1242/jcs.03443

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A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases

Center for Human Genetics, K.U.Leuven and Department of Molecular and Developmental Genetics, VIB, Herestraat 49, 3000 Leuven, Belgium

View larger version (28K): [in this window] [in a new window]   Fig. 1. Models of human PD-associated proteins. (A) -Synuclein is a 140 amino acid protein belonging to a family of related synucleins that includes β- and -synuclein. It has an N-terminal amphipathic region containing six imperfect repeats with a KTKEGV consensus sequence, a hydrophobic central region that contains the non-amyloid-β component (NAC) domain, and a highly acidic C-terminal tail containing several phosphorylation sites. (B) Parkin is a 465 amino acid protein that functions as an E3 ubiquitin ligase. It contains an N-terminal ubiquitin-like (UBL) domain that binds to RPN10 subunit of the 26S proteasome system, a central linker region, and a C-terminal RING domain comprising two RING finger motifs (RING1 and RING2) separated by an in-between-RING (IBR) domain. (C) DJ-1 is a highly conserved 189 amino acid protein that is ubiquitously and abundantly expressed in most mammalian tissues and belongs to the DJ-1/ThiJ/PfpI superfamily. (D) PINK1 is a highly conserved 581 amino acid protein that is ubiquitously expressed. It localizes to the mitochondria via an N-terminal mitochondrion-targeting motif (MTS). Furthermore, it shares sequence similarity with Ca2+/calmodulin-dependent protein kinase I and contains a catalytic serine/threonine kinase domain. (E) LRRK2 is a 2537 amino acid complex multi-domain protein that consists of a ankyrin-repeat region (ANK), an N-terminal leucine-rich repeat domain (LRR), a GTPase Roc domain (Roc) followed by associated C terminal of Roc (COR), a mitogen-activated kinase kinase kinase domain, and C-terminal WD40 repeat (approximately 40 amino acid repeats that form a β-propeller structure that might serve as a rigid scaffold for protein interactions). Approximate positions of missense mutations causing PD are indicated with arrows.

View larger version (54K): [in this window] [in a new window]   Fig. 2. Schematic representation of mitochondrial fusion and fission events. During fusion mitofusin 1 or 2 (Mfn1/2) proteins link two juxtaposed mitochondria through their coiled-coil domains. This is followed by outer, and subsequently inner, membrane fusion, which is GTP dependent and regulated by Opa1. During fission, Dnm1l is recruited from the cytosol to the outer mitochondrial membrane, where it interacts directly or indirectly with Fis1, leading to constriction of mitochondria and sequential separation of the inner and outer membrane.

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