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. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: Prog Neurobiol. 2013 Apr 30;0:17–32. doi: 10.1016/j.pneurobio.2013.04.004

Table 2.

Summary of mitochondrial dysfunction in familial PD

Gene Mitochondrial dysfunction Reference
α-synuclein
(PARK1,
SNCA)
(A53T or
overexpress
ion)

  1. causes accumulation of α-synuclein in mitochondria in specific regions

  2. mutant A53T human α-synuclein gene in mice causes mtDNA damage and respiratory complex IV impairment

  3. overexpression of wild-type human α- synuclein increases mitochondrial pathology in nigrostriatal dopaminergic neurons when exposed to low doses of MPTP

  4. mutant A53T human α-synuclein gene in cell lines reduces mitochondrial complex I activity

  5. mutant A53T human α-synuclein gene in mice increases sensitivity to mitochondrial toxins such as MPTP and paraquat

  6. overexpression of mutant A53T or wild-type human α-synuclein in cell lines causes mitochondrial association and leads to cytochrome c release, enhanced mitochondrial calcium and nitric oxide, and oxidative modification of mitochondrial components

  7. mitochondria of PD patients show accumulation of α-synuclein in substantia nigra and striatum, and decreased complex I activity

  1. (Li et al., 2007, Nakamura et al., 2008, Shavali et al., 2008, Zhang et al., 2008)

  2. (Martin et al., 2006)

  3. (Song et al., 2004)

  4. (Butler et al., 2012)

  5. (Norris et al., 2007, Thomas and Beal, 2007)

  6. (Parihar et al., 2008)

  7. (Devi et al., 2008)
Parkin
(PARK2)

  1. localizes in mitochondria where it binds to mitochondrial transcription factor (TFAM) to regulate mitochondrial transcription and replication

  2. overexpression prevents ceramide-induced mitochondrial swelling and cytochrome c release

  3. knockout mice have reduced mitochondrial complex I and IV activity

  4. homozygous parkin mutations in humans impair mitochondrial complex I and complex IV activities in leukocytes

  5. mice lacking parkin gene increases sensitivity to mitochondrial toxin, rotenone

  6. critical for mitochondrial dynamics and autophagy

  7. PINK1-parkin pathway promotes mitochondrial fission/ fusion and controls mitochondrial dynamics

  1. (Kuroda et al., 2006)

  2. (Darios et al., 2003)

  3. (Palacino et al., 2004)

  4. (Muftuoglu et al., 2004)

  5. (Rosen et al., 2006)

  6. (Narendra et al., 2008, Sun et al., 2012)

  7. (Clark et al., 2006, Deng et al., 2008) (Poole et al., 2008, Yang et al., 2008, Park et al., 2009, Yu et al., 2011)
PINK1
(PARK6)

  1. sub-localized in different regions including inner mitochondrial membrane, intermembrane space and outer mitochondrial membrane

  2. PINK1 knockout mice and human dopaminergic neurons have abnormalities in mitochondrial morphology, reduced membrane potential, increased ROS generation and high sensitivity to apoptosis

  3. PINK1 KO mice fibroblasts show low mitochondrial membrane potential, reduced cellular ATP levels and decline in mitochondrial respiratory activity

  4. PINK1 deficient mice showed reduction in complex I–IV activity

  5. PINK1 knockout mice show region-dependent alterations in mitochondrial proteins related to energy metabolism and membrane potential

  6. lack of PINK1 in Drosophila results in abnormal mitochondrial morphology, loss of nigrostriatal dopaminergic neurons, apoptotic muscle degeneration and enhances vulnerability to oxidative stress

  7. Loss causes mitochondrial defects, respiratory chain abnormalities and ATP synthesis defects in human peripheral tissues

  8. overexpression of PINK1 in restores normal mitochondrial morphology and inhibits ROS production

  9. overexpression of wild type PINK1 inhibits mitochondrial cytochrome c release and prevents neuronal apoptosis

  10. PINK1-parkin pathway promotes mitochondrial fission/ fusion and controls mitochondrial dynamics

  1. (Silvestri et al., 2005, Gandhi et al., 2006, Pridgeon et al., 2007)

  2. (Wood-Kaczmar et al., 2008)

  3. (Amo et al., 2011) (Exner et al., 2007)

  4. (Gautier et al., 2008)

  5. (Diedrich et al., 2011)

  6. (Clark et al., 2006, Park et al., 2006, Yang et al.,2006)

  7. (Hoepken et al., 2007)(Piccoli et al., 2008).

  8. (Wang et al., 2011)

  9. (Petit et al., 2005, Wang et al., 2007)

  10. (Clark et al., 2006, Deng et al., 2008) (Poole et al., 2008, Yang et al., 2008, Park et al., 2009, Yu et al., 2011)
DJ-1
(PARK7)

  1. DJ-1 knockout mice display a reduction in mitochondrial transmembrane potential and an increase in mitochondrial permeability transition pore opening

  2. DJ-1 null dopaminergic neurons show deficiency in mitochondrial complex I activity

  3. DJ-1 mutation cause impaired mitochondrial respiration, enhanced intra-mitochondrial ROS, reduced mitochondrial membrane potential, altered mitochondrial morphology and importantly, accumulation of defective mitochondria

  4. DJ-1 may support mitochondrial function during oxidative stress by interacting with several targets such as PINK1 and parkin

  5. DJ-1 activates transcription of Mn-SOD gene, which encodes for the mitochondrial antioxidant enzyme

  1. (Giaime et al., 2012)

  2. (Heo et al., 2012)(Kwon et al., 2011)

  3. (Krebiehl et al., 2010)

  4. (Tang et al., 2006) (Moore et al., 2005)

  5. (Zhong and Xu, 2008)
LRRK2 (PARK8)

  1. LRRK2 binds to outer mitochondrial membrane

  2. LRRK2 G2019S mutation causes defects in mitochondrial morphology and dynamics

  3. PD patients carrying LRRK2 G2019S mutation show a decrease in mitochondrial membrane potential and low total intracellular ATP levels in addition to mitochondrial elongation and interconnectivity

  1. (West et al., 2005, Biskup et al., 2006, Gloeckner et al., 2006)

  2. (Niu et al., 2012)

  3. (Mortiboys et al., 2010)

Please note all of the abbreviations are expanded when it appears first time in the text.