Dementia in Parkinson's disease is associated with enhanced mitochondrial complex I deficiency.

BACKGROUND: Dementia is a common feature of Parkinson's disease (PD), but the neuropathological changes associated with the development of Parkinson's disease dementia (PDD) are only partially understood. Mitochondrial dysfunction is a hallmark of PD but has not been studied in PDD. METHODS: Molecular and biochemical approaches were used to study mitochondrial activity and quantity in postmortem prefrontal cortex tissue. Tissues from pathologically confirmed PD and PDD patients and from age-matched controls were used to analyze the activity of mitochondrial enzyme complex nicotinamide adenine dinucleotide:ubiquinone oxidoreductase, or complex I (the first enzyme in the mitochondrial respiratory chain), mitochondrial DNA levels, and the expression of mitochondrial proteins. RESULTS: Complex I activity was significantly decreased (27% reduction; analysis of variance with Tukey's post hoc test; P < 0.05) in PDD patients, and mitochondrial DNA levels were also significantly decreased (18% reduction; Kruskal-Wallis analysis of variance with Dunn's multiple comparison test; P < 0.05) in PDD patients compared with controls, but neither was significantly reduced in PD patients. Overall, mitochondrial biogenesis was unaffected in PD or PDD, because the expression of mitochondrial proteins in patients was similar to that in controls. CONCLUSIONS: Patients with PDD have a deficiency in mitochondrial complex I activity and reduced mitochondrial DNA levels in the prefrontal cortex without a change in mitochondrial protein quantity. Therefore, mitochondrial complex I deficiency and reduced mitochondrial DNA in the prefrontal cortex may be a hallmark of dementia in patients with PD.

Mitochondrial retrograde signaling regulates neuronal function.

Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer's and Parkinson's. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson's disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.

Association of a polymorphism in mitochondrial transcription factor A (TFAM) with Parkinson's disease dementia but not dementia with Lewy bodies.

The single nucleotide polymorphism (SNP) A>G rs2306604 in the gene encoding mitochondrial transcription factor A (TFAM) has been associated with Alzheimer's disease, with the A allele being recognised as a risk factor, but has not been studied in other types of dementia. We hypothesised that TFAM SNP rs2306604 might also be associated with Lewy body dementias. To test this hypothesis rs2306604 genotype was determined in 141 controls and 135 patients with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD). rs2306604 genotype frequencies were significantly different to controls in PDD (p=0.042), but not in DLB (p=0.529). The A allele was also associated with PDD (p=0.024, OR=2.092), but not DLB (p=0.429, OR=1.308). Moreover, the A allele was strongly associated with PDD in males (p=0.001, OR=5.570), but not in females (p=0.832, OR=1.100). Mitochondrial DNA copy number in the prefrontal cortex was also significantly reduced in PDD patients, but this reduction was not associated with rs2306604 genotype. These data show that the TFAM SNP rs2306604 A allele may be a risk factor for PDD, particularly in males, but not for DLB. Therefore, the genetic factors that predispose individuals to develop dementia may differ in PDD and DLB.

Concerted control of gliogenesis by InR/TOR and FGF signalling in the Drosophila post-embryonic brain.

Glial cells are essential for the development and function of the nervous system. In the mammalian brain, vast numbers of glia of several different functional types are generated during late embryonic and early foetal development. However, the molecular cues that instruct gliogenesis and determine glial cell type are poorly understood. During post-embryonic development, the number of glia in the Drosophila larval brain increases dramatically, potentially providing a powerful model for understanding gliogenesis. Using glial-specific clonal analysis we find that perineural glia and cortex glia proliferate extensively through symmetric cell division in the post-embryonic brain. Using pan-glial inhibition and loss-of-function clonal analysis we find that Insulin-like receptor (InR)/Target of rapamycin (TOR) signalling is required for the proliferation of perineural glia. Fibroblast growth factor (FGF) signalling is also required for perineural glia proliferation and acts synergistically with the InR/TOR pathway. Cortex glia require InR in part, but not downstream components of the TOR pathway, for proliferation. Moreover, cortex glia absolutely require FGF signalling, such that inhibition of the FGF pathway almost completely blocks the generation of cortex glia. Neuronal expression of the FGF receptor ligand Pyramus is also required for the generation of cortex glia, suggesting a mechanism whereby neuronal FGF expression coordinates neurogenesis and cortex gliogenesis. In summary, we have identified two major pathways that control perineural and cortex gliogenesis in the post-embryonic brain and have shown that the molecular circuitry required is lineage specific.