Neurodegeneration and the m-AAA protease: pathogenic cascades in neurons and myelinating cells

The m-AAA protease is a hexameric complex involved in processing of specific substrates and turnover of misfolded polypeptides in the mitochondrial inner membrane. In humans, the m-AAA protease is composed of AFG3L2 and paraplegin. Mutations in AFG3L2 have been implicated in dominant spinocerebellar ataxia (SCA28) and recessive spastic ataxia-neuropathy syndrome (SPAX5). Mutations of SPG7, encoding paraplegin, are linked to hereditary spastic paraplegia. In the mouse, a third subunit AFG3L1 is expressed. Various mouse models recapitulate the phenotype of these neurodegenerative disorders, however, the pathogenic mechanism of neurodegeneration is not completely understood. Here, we studied several mouse models and focused on cell-autonomous role of the m-AAA protease in neurons and myelinating cells. We show that lack of Afg3l2 triggers mitochondrial fragmentation and swelling, tau hyperphosphorylation and pathology in Afg3l2 full-body and forebrain neuron-specific knockout mice. Moreover, deletion of Afg3l2 in adult myelinating cells causes early-onset mitochondrial abnormalities as in the neurons, but the survival of these cells is not affected, which is a contrast to early neuronal death. Despite the fact that myelinating cells have been previously shown to survive respiratory deficiency by glycolysis, total ablation of the m-AAA protease by deleting Afg3l2 in an Afg3l1 null background (DKO), leads to myelinating cell demise and subsequently progressive axonal demyelination. Interestingly, DKO mice show premature hair greying due to loss of melanoblasts. Together, our data demonstrate cell-autonomous survival thresholds to m-AAA protease deficiency, and an essential role of the m-AAA protease to prevent cell death independent from mitochondrial dynamics and the oxidative capacity of the cell. Thus, our findings provide novel insights to the pathogenesis of diseases linked to m-AAA protease deficiency, and also establish valuable mitochondrial dysfunctional mouse models to study other neurodegenerative diseases, such as tauopathies and demyelinating diseases.

Probing synechocystis-arsenic interactions through extracellular nanowires.

Microbial nanowires (MNWs) can play an important role in the transformation and mobility of toxic metals/metalloids in environment. The potential role of MNWs in cell-arsenic (As) interactions has not been reported in microorganisms and thus we explored this interaction using Synechocystis PCC 6803 as a model system. The effect of half maximal inhibitory concentration (IC50) [~300 mM As (V) and ~4 mM As (III)] and non-inhibitory [4X lower than IC50, i.e., 75 mM As (V) and 1 mM As (III)] of As was studied on Synechocystis cells in relation to its effect on Chlorophyll (Chl) a, type IV pili (TFP)-As interaction and intracellular/extracellular presence of As. In silico analysis showed that subunit PilA1 of electrically conductive TFP, i.e., microbial nanowires of Synechocystis have putative binding sites for As. In agreement with in silico analysis, transmission electron microscopy analysis showed that As was deposited on Synechocystis nanowires at all tested concentrations. The potential of Synechocystis nanowires to immobilize As can be further enhanced and evaluated on a large scale and thus can be applied for bioremediation studies.