Organelle Dysfunction and TNT-Mediated Aggregate Spreading in Neurodegeneration.

Area of Science:

• Neurobiology
• Cell Biology
• Pathology

Background:

• Neurodegenerative diseases (NDs) are marked by misfolded protein accumulation and spreading.
• Organelle dysfunction, particularly in lysosomes, mitochondria, and the endoplasmic reticulum (ER), is a key feature of NDs.
• These organelles are critical for proteostasis, metabolism, and stress signaling.

Purpose of the Study:

• To review organelle alterations in major NDs.
• To highlight the roles of lysosomes, mitochondria, and ER in protein aggregation.
• To explore intercellular protein transfer via tunneling nanotubes (TNTs) in ND progression.

Main Methods:

• Integrated review of scientific literature on organelle dysfunction and neurodegeneration.
• Focus on key proteins like alpha-synuclein and Tau.
• Examination of tunneling nanotubes (TNTs) as mediators of intercellular communication and aggregate spread.

Main Results:

• Organelle defects create conditions favoring protein aggregate formation and cellular vulnerability.
• TNTs facilitate the transfer of pathogenic protein aggregates between cells.
• TNT-mediated transfer impacts recipient cell pathways including autophagy, TFEB transcription, mitochondrial stress, and inflammation.

Conclusions:

• Organelle dysfunction and TNT-mediated communication are intertwined drivers of ND progression.
• Targeting organelle function and limiting aggregate spread via TNTs are potential therapeutic strategies for NDs.