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Neurological dysfunction in LSDs has historically been attributed to the disruption of neuronal and glial homeostasis resulting from the progressive jamming of the endosomal\/lysosomal pathway. In neurons, a dysfunctional endosomal\u2013lysosomal system can elicit dire consequences. Given 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 common features during the early stages in many LSDs, particularly sphingolipidoses. In essence, failure of synapses to convey their messages, even without major structural damage to the neuronal bodies, is a form of physiological death. This concept of dying\u2010back neuropathology is highly relevant not only for understanding the dynamics of the neurological decline in these diseases, but, more importantly; it might also constitute an important target for molecular therapies to protect perhaps the \u201cAchilles\u201d point in the entire physiological architecture of the brain, thus avoiding an irreversible journey to neuronal demise. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jnr.23753","type":"journal-article","created":{"date-parts":[[2016,9,17]],"date-time":"2016-09-17T11:22:31Z","timestamp":1474111351000},"page":"1031-1036","source":"Crossref","is-referenced-by-count":14,"title":["Synaptic failure: The achilles tendon of sphingolipidoses"],"prefix":"10.1002","volume":"94","author":[{"given":"Ludovico","family":"Cantuti\u2010Castelvetri","sequence":"first","affiliation":[{"name":"Max Planck Institute of Experimental Medicine, Department of Cellular and Molecular Neurobiology G\u00f6ttingen 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