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Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites.
Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction Ann parkinson nude long been implicated in the etiopathogenesis of Parkinson's disease PDbased on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models.
Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Ann parkinson nude on the function and dysfunction of these genes revealed that various aspects Ann parkinson nude mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control.
Parkinson's disease PD is a heterogeneous neurodegenerative disease entity typically diagnosed by its cardinal motor symptoms, including bradykinesia, hypokinesia, rigidity, resting tremor, and postural instability, which are subsumed under the syndrome of parkinsonism.
The motor manifestations are attributable to the degeneration of dopaminergic DA neurons within the substantia nigra pars compacta SNcresulting in dopamine depletion and derangements of neuronal circuits in the basal ganglia target regions of these neurons. The role of Ann parkinson nude bodies in the pathogenic process is discussed controversially. Parkinsonism can occur in the absence of Lewy bodies, for instance in some cases of familial PD or in drug-induced parkinsonism Davis et al, ; Langston et al, ; Nuytemans et al, On the other hand, Lewy body pathology is sometimes found at autopsy in individuals without reported symptoms of parkinsonism Jellinger, ; Adler et al, The manifestation of non-motor symptoms, some of which even precede the motor symptoms, reflect the fact that the neurodegenerative process is not limited to the SNc but has a much wider impact.
Non-motor symptoms, such as autonomic dysfunction, sleep abnormalities, depression, and dementia, can contribute considerably to disability, as they usually are not responsive to dopamine replacement therapy. The etiopathogenesis of sporadic PD, the most common form of parkinsonism, is complex with variable contributions of genetic susceptibility and environmental factors Figure 1. Ageing is one of the most important risk factors for sporadic PD.
Given the demographic trend towards an aged population, the prevalence of PD and thus its socioeconomic burden will increase dramatically in the next decades. Over the last 15 years enormous effort has been taken to unravel the role of genetics in PD pathogenesis.
Linkage analyses discovered six genes associated with Mendelian forms of parkinsonism, and genome-wide association studies identified susceptibility genes contributing to the risk for sporadic PD.
The identification of genes associated with parkinsonism has had a major Ann parkinson nude on PD research, allowing to dissect molecular pathways implicated in the pathogenesis.
From genetic cellular and animal models, it emerged that mitochondrial alterations, oxidative stress, and impaired clearance of misfolded proteins and damaged organelles by proteasomal and lysosomal degradation pathways contribute to the disease process reviewed in Dawson et al, ; Corti et al, ; Martin et al, ; and Shulman et al, Moreover, there is increasing evidence that sporadic and familial variants of PD share some common pathways that converge at mitochondria reviewed in Abou-Sleiman et al, ; Lin and Beal, ; Mandemakers et al, ; Bogaerts et al, ; Henchcliffe and Beal, ; Schapira, ; Vila et al, ; Van Laar and Berman, ; Bueler, ; Burbulla et al, ; Winklhofer and Haass, ; and Schon and Przedborski, In the following, we will review our current knowledge on the role of mitochondria in PD pathogenesis and how these insights have changed our conceptional thinking and may eventually be translated into novel neuroprotective approaches.
Aetiology of Parkinson's disease PD and possible links to mitochondrial integrity. Familial Ann parkinson nude is caused by mutations in genes identified by linkage analyses that are inherited in an autosomal recessive or dominant manner. Sporadic PD is considered to be a complex neurodegenerative disease entity with both genetic susceptibility and environmental factors contributing Ann parkinson nude the etiopathogenesis.
Both genetic and environmental factors influence various mitochondrial aspects, such as bioenergetics, dynamics, transport, and quality control. The first link between parkinsonism and mitochondria became evident in the early s, when it was discovered that a neurotoxin causing a parkinsonian syndrome inhibits mitochondrial respiration. Although MPTP-induced parkinsonism results from an acute toxic insult and therefore differs from the slow and progressive disease process in sporadic PD, the impact of MPTP has been far reaching.
In particular, MPTP and other complex I inhibitors such as rotenone are still being used to model PD in animals and to evaluate therapeutic approaches reviewed in Hirsch, ; Bezard and Przedborski, ; and Cannon and Greenamyre, Interestingly, consumption of fruit Ann parkinson nude herbal teas from plants of the Annonceae family, containing the complex I inhibitor annonacin, has been linked to the high frequency of atypical parkinsonism in Guadeloupe Caparros-Lefebvre and Elbaz, ; Lannuzel et al, ; Champy et al,further substantiating a causal role of mitochondrial Ann parkinson nude in the pathogenesis of at least some parkinsonian syndromes.
In mitochondrial preparations from PD frontal cortex samples, complex I subunits derived from both mitochondrial and nuclear genomes were found to be oxidatively damaged, reflected by an increase in protein carbonyls Keeney et al, In a mouse model of mild complex I deficiency induced by the dopamine neuron-specific loss of the Ndufs4 subunit, increased striatal dopamine turnover rates and decreased dopamine release from striatal axon terminals have been observed Sterky et al, These alterations in striatal dopamine homeostasis may be caused by a reduced vesicular uptake of dopamine due to ATP deficiency followed by enhanced cytosolic dopamine metabolism, suggesting that impaired dopamine release may be an early consequence of mitochondrial impairment Choi et al, ; Sterky et al, Mitochondrial oxidative phosphorylation depends on both mitochondrial and nuclear DNA-encoded proteins.
Mutations in mtDNA can be either inherited maternally or acquired and typically cause variable phenotypes in cells with high energy demands, such as neurons and muscle cells. Mouse models with defects in genes essential Ann parkinson nude the maintenance of mtDNA support the notion that alterations in the mitochondrial genome cause respiratory chain deficiencies and phenotypes associated with ageing and age-related diseases reviewed in Reeve et al, ; Larsson, ; and Park and Larsson, Notably, cosegregation of parkinsonism with mutations in the human POLG1 gene Ann parkinson nude been reported in several families reviewed in Orsucci et al, In support of a causative role of mitochondrial dysfunction in PD, mice with a DA neuron-specific deletion of the mitochondrial transcription factor TFAM, which is essential for mitochondrial transcription and maintenance of Ann parkinson nude, develop a parkinsonian phenotype reproducing key features of PD: Similarly, expression of mitochondrially targeted Pst I endonuclease in DA neurons, which induces double-strand breaks in mtDNA, causes Ann parkinson nude neuronal degeneration and striatal dopamine depletion Pickrell et al, An age-dependent increase in mtDNA deletions has been found in individual DA neurons dissected from the SNc of post mortem human brain Bender et al, ; Kraytsberg et al, Different types of mtDNA deletions were found in the same individual, but each neuron contained only a single mtDNA mutation, indicating that the mutation was acquired and clonally expanded.
Moreover, SNc neurons seem to be particularly vulnerable to mtDNA mutations, since hippocampal neurons or pyramidal cortical neurons of aged individuals did not contain high levels of mtDNA mutations. However, it seems quite plausible that mtDNA mutations accumulate in the course of the disease as a consequence of an increase in cellular stress and mitochondrial replication errors along with a decrease in the fidelity of quality control systems.
Once the mtDNA mutations surpass a critical threshold, the resulting respiratory deficiency may contribute to neuronal degeneration and cell death. According to a widespread concept, inhibition of complex I decreases mitochondrial ATP production and increases the formation of reactive oxygen species ROSwhich damage mtDNA, components Ann parkinson nude the respiratory chain and other mitochondrial factors, thereby triggering a vicious circle between mitochondrial impairment and oxidative stress reviewed in Abou-Sleiman et al, ; Lin and Beal, ; and Henchcliffe and Beal, This model has been particularly popular to explain the increased vulnerability of SNc DA neurons, since this neuronal population is characterized by a high oxidative burden and a low anti-oxidant capacity.
However, an obligatory link between mitochondrial dysfunction and increased ROS production has been questioned based on weak experimental support for such a scenario in vivo reviewed in Fukui and Moraes, ; Gems and Doonan, ; and Park and Larsson, For example, rotenone toxicity has been reported to be caused by spare respiratory capacity rather than oxidative stress.
In Ann parkinson nude neurons, rotenone does increase the formation of mitochondrial superoxide, Ann parkinson nude, trapping superoxide fails to reduce rotenone toxicity Yadava and Nicholls, In addition, various mouse models with severe respiratory chain deficiency display increased apoptotic cell death but not increased ROS formation or oxidative stress Wang et al, ; Kujoth et al, ; Trifunovic et al, ; Kruse et al, Moreover, ROS are not always harmful agents, they also act as important signal transducers in a variety of biological processes.
The parkin gene has been identified in as a causative gene for autosomal recessive parkinsonism Kitada et al, More than pathogenic parkin mutations have been reported, accounting for the majority of autosomal recessive parkinsonism.
Moreover, the cysteine-rich RBR domain renders parkin vulnerable to inactivation by severe oxidative stress Winklhofer et al, ; LaVoie et al, ; Wong et al, ; Schlehe et al, Oxidatively modified, misfolded parkin has indeed been found in the brains of PD patients, suggesting that inactivation Ann parkinson nude parkin may also play a role in sporadic PD Pawlyk et al, ; Chung et al, ; Yao et al, ; LaVoie et al, ; Wang et al, a.
In support of this notion, the c-Abl tyrosine kinase has been reported to be activated in DA neurons of sporadic PD patients, leading to the phosphorylation and inactivation of parkin Ko et al, ; Imam et al, The presence of the RBR domain suggested that parkin acts as an E3 ubiquitin ligase, mediating the covalent attachment of ubiquitin moieties to substrate proteins Shimura et al, ; Zhang et al, Considerable evidence has Ann parkinson nude accumulated indicating that parkin can catalyse various modes of ubiquitination, including poly-ubiquitination with different lysine linkages or mono-ubiquitination.