SPG11 and SPG15 HSP mechanism explained

Lysosomes and waste removal in cells impaired


In SPG11 and 15, loss of key proteins results in depletion of lysosomes and functions related to them as the primary causes of neurodegeneration.


Craig Blackstone
Craig Blackstone

Autophagy (cells getting rid of their own waste through the lysosomes) allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis (balance).


Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance.


Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate.


Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.


SOURCE: J Clin Invest. 2014 Nov 3. pii: 77598. doi: 10.1172/JCI77598. [Epub ahead of print] PMID: 25365221 [PubMed – as supplied by publisher]

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation.

Chang J, Lee S, Blackstone C.

Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.



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