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Protein aggregation and autophagy dysfunction: new lessons from mucopolysaccharidoses

Antonio Monaco1, Alessandro Fraldi1

  • 1CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Translational Medicine, University of Naples "Federico II", Naples, Italy.

Autophagy
|August 19, 2021
PubMed

Insights

Mucopolysaccharidoses (MPS) cause neurodegeneration due to impaired autophagy. Amyloid aggregation in neurons, a result of GAG storage, further disrupts autophagosome clearance in Sanfilippo syndrome.

Area of Science:

  • Neuroscience
  • Metabolic Disorders
  • Cell Biology

Background:

  • Mucopolysaccharidoses (MPS) are inherited metabolic diseases characterized by neurological impairment.
  • Defects in lysosomal enzymes lead to glycosaminoglycans (GAGs) accumulation, causing cellular dysfunction.
  • Impaired macroautophagy/autophagy is a known driver of neurodegeneration in MPS, but the mechanisms are unclear.

Purpose of the Study:

  • To investigate the mechanisms underlying autophagy dysfunction in MPS.
  • To explore the relationship between GAG storage, amyloid aggregation, and autophagosome clearance in neuronal cells.

Main Methods:

  • Utilized a mouse model for MPS-III (Sanfilippo syndrome).
  • Analyzed the progression of GAG storage and amyloid protein aggregation in neuronal cell bodies.
  • Assessed the impact of these pathological events on the autophagy pathway, specifically lysosomal-dependent autophagosome clearance.

Main Results:

  • GAG storage precedes and triggers progressive amyloid protein aggregation in neuronal cell bodies.
  • Amyloid aggregation impairs the autophagy pathway.
  • This impairment specifically affects lysosomal-dependent autophagosome clearance.

Conclusions:

  • Amyloid aggregation is a key downstream event in MPS neurodegeneration, directly impacting autophagy.
  • Understanding this mechanism provides new insights into the pathogenesis of Sanfilippo syndrome and potential therapeutic targets for MPS-related neurodegeneration.
Keywords:
Autophagylysosomal storage diseaseslysosomemucopolysaccharidosesprotein aggregation

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