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Advisor(s)
Abstract(s)
Our perception of the lysosome and its role in the cell has suffered a tremendous change since its discovery by Christian de Duve, 60 years ago. Traditionally depicted as cell's waste bin, this small organelle used to be regarded as just an end-point degradative compartment. Nevertheless, the early discovery of a group of rare life-threatening diseases which resulted from failures in that degradation process, the so-called Lysosomal Storage Disorders (LSDs), prompted the search for the underlying causes of such abnormalities and led to a greater understanding of lysosomal function and physiology. Nowadays, the lysosome is no longer viewed as a terminal organelle, but rather as the central regulator of cellular metabolic homeostasis, coordinating a very complex and interactive set of intracellular organelles that have a wide array of specialized functions: the endosomal-lysosomal system.
During this same period, lysosomal dysfunction was also extensively documented in other diseases that afflict a much higher number of individuals than all LSDs together. The first clues on this association came from the recognition that Gaucher disease (GD) patients had a higher risk of developing multiple myeloma and/or PD. Numerous reports over the last decades have focused the comorbidity between this GD and either of those common conditions. But GD patients are far from being the only individuals afflicted by an LSD, who present a higher risk of developing a second disorder. There are several case reports of both patients and carriers of specific LSDs presenting with neuropathological findings suggestive of PD (-synuclein accumulation and inclusions, as well as loss of neurons in the substantia nigra), for example. Recently, that same 'risk association' was also documented for patient cohorts of Niemann-Pick type C, Mucopolysaccharidosis type III C and Fabry disease and the idea that a more general mechanism relating lysosomal dysfunction and the development of -synuclein aggregation disorders exists, is gaining supporters.
Additional striking connections between common diseases and rare LSD are being unveiled nowadays. Mutations in one of the genes which is long-known to cause frontotemporal dementia (the most common cause of dementia in people under age 65) when mutated in one of its alleles, were recently shown to cause a novel LSD, neuronal ceroid lipofuscinosis 11, when affecting both its copies.
In summary, we have come a long way since the first descriptions of LSDs were published and their underlying biochemical basis unveiled. Parallels across groups of traditionally unrelated neurological disorders have emerged, reshaping the way we think about the role of the lysosome and the whole system it controls. Pathophysiological boundaries have blurred between LSDs and other disorders including both early-onset neurogenetic conditions and late-onset neurodegenerative diseases. Ultimately, a better understanding of lysosomal dysfunction in all these conditions may provide valuable insights towards the development of therapeutic strategies for a multitude of presently untreatable disorders. So, let us wait for the next 60 years, and hope they will be as groundbreaking as the last ones.
Description
Keywords
Doenças Genéticas Lysosomal storage disorders (LSDs) Gaucher disease (GD) Neuronal ceroid lipofuscinosis (NCL) Cancer Parkinson's disease (PD) Frontotemporal lobar degeneration (FTLD)
Pedagogical Context
Citation
Publisher
Instituto Nacional de Saúde Doutor Ricardo Jorge, IP