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Knupp A, Mishra S, Martinez R, Braggin JE, Szabo M, Kinoshita C, Hailey DW, Small SA, Jayadev S, Young JE. Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing. Cell Rep. 2020 Jun 2;31(9):107719. PubMed.
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The work from Jessica Young’s group is elegant and adds further to the wealth of evidence that place SORL1 as a central player in Alzheimer’s disease.
They find that when neurons derived from iPSCs are genetically modified to inactivate SORL1, they show trafficking and processing defects of APP, confirming previous findings by others and us, and that SORLA determines endosomal trafficking of APP. However, the current study now links yet another AD pathology to SORL1 activity, as these neurons display enlarged endosomes, similar to the cytopathology hallmark for neurons from AD brains. Interestingly, endosomal enlargement following SORL1 inactivation was only found in neurons but not in microglia. This finding is in line with our paper from last year, which reported SORL1 silencing leading to enlarged (and dysfunctional) lysosomes in only some cells (Pietilä et al., 2019).
SORL1 is (misleadingly?) often referred to as a ”microglia gene.” This is likely due to high transcript levels seen in activated microglia in AD brains. However, it is well known that for many genes there is little correlation between transcript and translated protein levels. And to date there is no proof that SORLA has any functional role in microglia. This paper by the Young group does not change that, although this is now the first time that SORLA protein expression was demonstrated for human microglia.
Future studies should aim to determine if SORLA has any function in this cell type. However, all evidence so far points to neuronal functions of SORLA, and the current paper provides further support for how SORL1 inactivation leads to neuronal defects, which in my view is critical for understanding the link between SORL1 and Alzheimer’s disease.
Pietilä M, Sahgal P, Peuhu E, Jäntti NZ, Paatero I, Närvä E, Al-Akhrass H, Lilja J, Georgiadou M, Andersen OM, Padzik A, Sihto H, Joensuu H, Blomqvist M, Saarinen I, Boström PJ, Taimen P, Ivaska J. SORLA regulates endosomal trafficking and oncogenic fitness of HER2. Nat Commun. 2019 May 28;10(1):2340. PubMed.View all comments by Olav Andersen
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