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SYNAPTIC FAILURE: THE ACHILLES TENDON OF SPHINGOLIPIDOSES #MMPMID27638588
Cantuti-Castelvetri L; Bongarzone ER
J Neurosci Res 2016[Nov]; 94 (11): 1031-6 PMID27638588show ga
The presence of life-threatening neurological symptoms in more than two thirds of lysosomal storage disease (LSDs) underlines how vulnerable the nervous system is to lysosomal failure. Neurological dysfunction in LSDs has historically been attributed to the disruption of neuronal and glial homeostasis due to the progressive jamming of the endosomal/lysosomal pathway. In neurons, a dysfunctional endosomal-lysosomal system can elicit dire consequences. Considering that neurons are largely postmitotic after birth, one can clearly understand that the inability of these cells to proliferate obliterates any possibility of diluting stored lysosomal material by means of cellular division. At its most advanced stage, this situation constitutes a terminal factor in neuronal life, resulting in cell death. However, synaptic deficits in the absence of classical neuronal cell death appear to be a common feature during the early stages in many LSDs, particularly sphingolipidoses. In essence, failure of synapses to convey their messages, even without major structural damage of the neuronal bodies, is a form of physiological death. This concept of dying back neuropathology is not only highly relevant for understanding the dynamics of the neurological decline in these diseases, but more importantly, it may constitute an important target for molecular therapies to protect perhaps the ?Achilles? point in the entire physiological architecture of brain and avoid an irreversible journey to neuronal demise.
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J+Neurosci+Res 2016 ; 94 (11): 1031-6
