TFEB, the lysosome master switch

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Marie Decressac, Bengt Mattsson, Pia Weikop, Martin Lundblad, Johan Jakobsson and Anders Björklund (senior author) at Lund University, Sweden (Björklund's lab; other authors' affiliations not checked). Björklund's work on TFEB and miR-128 had a 2011 Michael J. Fox Foundation grant.

What happened

In an AAV-alpha-synuclein rat model (synuclein over-expressed in the nigra, see landmark 41), the abstract reports that the damage was tied to a progressive decline in lysosome markers and to TFEB being held in the cell's cytoplasm instead of entering the nucleus. TFEB is a switch that turns on genes for lysosomes (the cell's recycling bins) and autophagy (self-cleaning). Overexpressing TFEB reversed the lysosome changes and protected dopamine neurons by clearing synuclein oligomers (small clusters). A microRNA that dampens TFEB, miR-128, made neurons more vulnerable. Starting the drug-type activation late, by blocking mTOR (a growth-signalling enzyme that restrains autophagy), halted synuclein-induced degeneration and further progression. Human Parkinson's midbrain showed similar lysosome changes. PNAS 2013;110(19):E1817–E1826, DOI 10.1073/pnas.1305623110, PMID 23610405.

Why it moved us toward a cure

It shifted "help the cell clear synuclein" from a general idea to a testable target: raise the cell's whole lysosome capacity, rather than one enzyme. It fits the clearance failures in landmark 59 and landmark 35, and the lysosomal damage pathways in landmark 96.

Outcome

Open. All the evidence is in a rat model with strong over-expression of synuclein, and the effect sizes were not checked. No TFEB-activating drug in human Parkinson's trials was found. No correction or retraction was found in Crossref or Europe PMC (PubPeer could not be reached); no independent replication was checked. Ambroxol (landmark 40) is a different, enzyme-focused lysosomal approach.

Sources

• Decressac et al., PNAS 2013;110:E1817–E1826, DOI 10.1073/pnas.1305623110 · PubMed 23610405 · Alzforum entry
• Decressac & Björklund, "TFEB: Pathogenic role and therapeutic target in Parkinson disease," Autophagy 2013;9:1244–1246
• Michael J. Fox Foundation grant summary (Björklund, 2011)
• Not yet verified: the paper's own numbers (only the abstract was read); the absence of TFEB-targeted trials; the authors' institutions.