PMC:3023298 / 103251-109741
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3023298","sourcedb":"PMC","sourceid":"3023298","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3023298","text":"PD α-Syn Tg Mice Develop Neuronal Mitochondrial Degeneration and Cell Death\nInformation gleaned from molecular genetic studies of human genes linked to familial PD drives experimental work on the generation of animal and cell models of PD. Parkin null mice appear to have a normal lifespan, do not develop any major neurological abnormalities, and have no loss of midbrain dopaminergic neurons and no formation of inclusions [382,383]. However, parkin-/- mice exhibit some evidence of dopaminergic presynaptic dysfunction in striatum and possible deficits in behavioral tests indicative of nigrostriatal dysfunction [382], although this finding has not been confirmed in another mouse line [383]. Parkin-/- mice have decreases in proteins involved in mitochondrial oxidative phosphorylation and oxidative stress in ventral midbrain and exhibit reduced mitochondrial respiration in striatum, but they have no mitochondrial ultrastructural abnormalities [384]. In contrast, tg mice expressing the Parkin Q311X truncation mutation develop a progressive hypokinetic disorder, degeneration of SNc neurons, and loss of striatal dopamine [385]. Thus, Parkin could be important for maintenance of mitochondrial function or mitochondrial turnover through autophagy and synaptic integrity distally within the SNc neuron target region.\nMice with null mutations in DJ-1 also have a normal lifespan and do not develop an overt phenotype or loss of dopaminergic neurons, but behavioral tests reveal age-dependent motor deficits and neurochemical assessment shows altered striatal dopamine content [386]. DJ-1 null mice also show altered D2 dopamine receptor-mediated function [387].\nSeveral tg mouse lines have been made using different promoters to drive expression of human full-length wild-type or mutant α-Syn [349,388,389,390,391,392,393]. Of these mouse lines, tg mice expressing human A53T mutant α-Syn have a shortened lifespan and develop a severe movement disorder and synucleinopathy [349,390,393]. It is noteworthy that there have been no reports of robust dopamine SNc neuron degeneration in full-length α-Syn tg mice. However, tg mice expressing a truncation mutant of human α-Syn show a development-related loss of SNc neurons [394]. Cell death mechanisms or thresholds for cell death activation in human and mouse brain dopamine neurons might differ.\nDespite the absence of prominent changes in the SNc, tg α-Syn mice do develop robust cell death and neuronal loss in other regions of brain and in spinal cord [395]. These tg mice express high levels of human wild-type or mutant (A53T and A30P) α-Syn under the control of the mouse prion protein promoter [390]. Mice expressing A53T α-Syn (lines G2-3 and H5), but not mice expressing wild-type (line I2-2) or A30P (line O2) α-Syn, develop adult-onset progressive motor deficits, including reduced spontaneous activity with bradykinesia, mild ataxia and dystonia, at ~10–15 months of age followed by rapidly progressive paralysis and death [390]. A53T mice develop intraneuronal inclusions, mitochondrial degeneration, and cell death in neocortex, brainstem, and spinal cord [395]. Brainstem neurons and spinal motor neurons display a prominent chromatolysis reaction and axonal spheroids, typical of that seen after axonal injury [396]. A53T mice form LB-like inclusions in neocortical and spinal motor neurons and have progressive, profound loss (~75%) of motor neurons that causes their paralysis [341,395].\nMitochondrial pathology in A53T mice involving mitochondrial DNA damage is seen frequently in the absence of nuclear DNA damage in large brainstem neurons and spinal motor neurons [395]. Subsets of mitochondria in brainstem and spinal cord cells in A53T mice appear dysmorphic, becoming shrunken, swollen, or vacuolated [395]. Human α-Syn is found bound to some mitochondria in degenerating neurons in A53T mice [395]. Some abnormal intracellular inclusions in these cells are degenerating mitochondria. A mitochondrial defect in A53T mice is further indicated by biochemical evidence revealing loss of complex IV activity [395].\nThe mechanisms for this mitochondrial DNA damage are possibly related to oxidative stress. The presence of oxidative stress in mutant α-Syn tg mice is shown by evidence that mitochondrial associated metabolic proteins are oxidized in A30P mice [397]. α-Syn can generate H2O2 [398] and •OH [399] in vitro upon incubation with Fe(II). There is evidence for ONOO--mediated oxidative/nitrative stress in A53T mouse motor neurons, as indicated by the presence of nitrated human synuclein [395]. Nitrated synuclein forms inclusions in motor neurons consistent with in vitro data showing that ONOO- promotes the formation of stable α-Syn oligomers [400,401]. The evidence for mitochondrial DNA damage is consistent with the presence of ONOO- or its derivatives near mitochondria, because ONOO- or products of ONOO- are directly genotoxic by causing single- and double-strand breaks in DNA [13]. Moreover, the loss of complex IV enzyme activity without a change in protein level [395] might be explained by inactivation of this mitochondrial enzyme by nitration. Overall, ONOO- mediated damage in mitochondria could be a key pathological mechanism leading to motor neuron degeneration in A53T mice.\nThe reasons for the vulnerability of mouse motor neurons to human A53T mutant α-Syn are not clear. These mice express high levels of mRNA and protein for human α-Syn in the forebrain, diencephalon, and midbrain [390], but these regions are much less vulnerable than spinal cord. A53T α-Syn causes axonopathy [349,393], thus motor neuron vulnerability could be related to their long myelinated axons and interactions with oligodendrocytes and Schwann cells for myelin support. Motor neuron vulnerability could also be related to their unusual expression of inducible NOS (iNOS) in mitochondria [381,402]. Moreover, distal axonopathy and muscle disease may have roles in the pathogenesis in A53T mice [395]. Prominent skeletal muscle denervation occurs in α-Syn tg mice [393,395]. This work is intriguing because the original goal was to develop a tg mouse model of PD, but the result is a mouse model of ALS. Thus, the mutant α-Syn A53T tg mouse is a new model to study mechanisms of motor neuron degeneration and could provide insight into the selective vulnerability of motor neurons in age-related disorders and the possible roles of α-Syn in synaptic maintenance and diseases of long-axon neurons 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