Dinkel L, Hummel S, Zenatti V, Malara M, Tillmann Y, Colombo A, Monasor LS, Suh JH, Logan T, Roth S, Paeger L, Hoffelner P, Bludau O, Schmidt A, Müller SA, Schifferer M, Nuscher B, Njavro JR, Prestel M, Bartos LM, Wind-Mark K, Slemann L, Hoermann L, Kunte ST, Gnörich J, Lindner S, Simons M, Herms J, Paquet D, Lichtenthaler SF, Bartenstein P, Franzmeier N, Liesz A, Grosche A, Bremova-Ertl T, Catarino C, Beblo S, Bergner C, Schneider SA, Strupp M, Di Paolo G, Brendel M, Tahirovic S. Myeloid cell-specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease. Sci Transl Med. 2024 Dec 4;16(776):eadl4616. Epub 2024 Dec 4 PubMed.
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University College Cork
Dinkel et al. conducted a valuable study examining the health impact of cell-type-specific loss of NPC1 protein in myeloid cells (microglia and peripheral immune cells, Npc1flox/flox; Cx3cr1Cre (Cre+)) compared to whole-body NPC1 knockout (-/-) mice. This is the first study of its kind to investigate the cell-autonomous vs. non-autonomous role of microglia in NPC1 neuropathology. As expected, brain tissue from the conditional Cre+ NPC1-KO mice had extensive increases in lipids, including bis(monoacylglycero) phosphate, glycosphingolipids, and unesterified cholesterol, and proteins such as p62 that are normally degraded within the endosomal-autophagic-lysosomal (EAL) network. However, Cre+ NPC1-KO mice did not have extensive demyelination in their brains, or a loss of cerebellar Purkinje neurons, both classical features of whole-body NPC1 knockout (-/-) mice and human NPC cases. It was previously reported by Lieberman and colleagues that the cell-specific loss of NPC1 in neurons was sufficient to cause most neuropathological features of NPC1 disease (Elrick et al., 2010; Yu et al., 2011), however, findings from Dinkel et al. suggest that though NPC1 microglia are not the main driving force for neurodegeneration, they do contribute to neuroinflammation, astrogliosis, and reduced glucose metabolism, which warrants further exploration.
I have some reservations about the use of the term “hyperactive microglia” in this study, as a loss of NPC1 is known to cause more sluggish lysosomal digestive capacity, which would impair phagocytosis. I think more work needs to be done to characterize the functional state of lysosomal flux in microglia in these studies, and in those for AD models, as the functional phenotypes of microglia may be misinterpreted if not fully characterized. For example, immune cells can become activated by external stimuli, including pathogens and damage-associated molecular patterns (DAMPs), but they may also show signs of stress when internal lysosomal flux capacity is compromised, as is the case in lysosomal storage diseases such as NPC1. I think a limitation on this paper is that a large emphasis was placed on assuming that “hyperactive microglia” were driving some neuropathology in the KO mice, where it is also possible that impaired lysosomal flux in the NPC1-KO microglia and peripheral immune cells, which may stem from impaired phagocytosis, could lead to other stress-related responses that impact neurons in the brain. Without the inclusion of functional phagocytosis assays on the NPC1-KO microglia, we do not know if they are hyperactive or hypoactive.
From a therapeutic perspective, the beneficial effects N-acetyl-l-leucine on blood-derived macrophages from patients with NPC1, was very promising. NALL treatment increased the clearance of exogenously applied Aβ aggregates and reduced the accumulation of TSPO, a mitochondrial protein whose accumulation can be an indication of impaired mitophagy (Frison et al., 2021). These findings suggest NALL can restore immune cell function in NPC1 patients and possibly in people with other neurodegenerative diseases where impaired lysosomal flux underlies neuronal dysfunction.
References:
Elrick MJ, Pacheco CD, Yu T, Dadgar N, Shakkottai VG, Ware C, Paulson HL, Lieberman AP. Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration. Hum Mol Genet. 2010 Mar 1;19(5):837-47. Epub 2009 Dec 10 PubMed.
Frison M, Faccenda D, Abeti R, Rigon M, Strobbe D, England-Rendon BS, Cash D, Barnes K, Sadeghian M, Sajic M, Wells LA, Xia D, Giunti P, Smith K, Mortiboys H, Turkheimer FE, Campanella M. The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity. Mol Psychiatry. 2021 Mar 4; PubMed.
Yu T, Shakkottai VG, Chung C, Lieberman AP. Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration. Hum Mol Genet. 2011 Nov 15;20(22):4440-51. Epub 2011 Aug 19 PubMed.
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