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Klein ZA, Takahashi H, Ma M, Stagi M, Zhou M, Lam TT, Strittmatter SM. Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron. 2017 Jul 19;95(2):281-296.e6. PubMed.
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DZNE-German Center for Neurodegenerative Disease
Zoe A. Klein and colleagues in Stephen Strittmatter's lab show that deficiency of TMEM106B partially rescues the lysosomal effects of knocking out progranulin (Grn) in mice.
Klein et al. show that in Grn knockout mice, increased levels of lysosomal hydrolases, which have been reported previously by several research groups, result in enhanced enzyme activity and consequently in enhanced protein degradation via the lysosomal pathway.
Interestingly, they convincingly showed that loss of TMEM106B has an opposite effect on activity of lysosomal enzymes. However, only two out of three analyzed hydrolases show a reduced activity and thereby provide a kind of rescue phenomenon of this particular effect in Grn knockout mice.
That the loss of TMEM106B rescues the enhanced lysosomal activity in the Grn KO mouse due to less acidification in lysosomes is a quite exciting finding. However, the data that TMEM106B stabilizes the Vo subunit of the vATPase appear somewhat weak, as neither the endogenous V-ATPase Vo or AP1 subunits could be shown on immunoblot. Less acidic lysosomes are expected to change the maturation of many lysosomal hydrolases, which is unfortunately not shown.
Furthermore, impaired lysosomal acidification most likely results in impaired lysosomal and autophagic protein degradation and finally in a lysosomal storage disease. For example, this has been suggested for CLN3 mutations (Gachet et al., 2005), which are associated with juvenile Batten disease.
Thus, it may not be a good option to treat a neuronal ceroid lipofuscinosis (NCL) caused by the total loss of Grn with inhibition of lysosomal acidification either with alkalizing drugs or by altering TMEM106B expression, thereby further impairing protein degradation. The most critical question which needs to be answered before deciding on a treatment is how enhanced degradation caused by Grn deficiency results in a neuronal lysosomal storage phenotype.
No lysosomal storage disease has been described yet as being the result of enhanced lysosomal function.View all comments by Anja Capell
Penn Neurological Institute
Since the advent of the genome-wide association study, we've found many genetic risk factors for diseases, including TMEM106B as a common variant genetic risk factor for frontotemporal dementia. However, it has been hard to understand what these risk factors do, and how our finding them can ever help a person with that disease.
An interesting aspect of this paper is that it looks at TMEM106B as a genetic modifier for a Mendelian gene in which haploinsufficiency mutations cause FTD with high penetrance, the GRN gene. The authors show through the use of mouse models that the interaction between GRN and TMEM106B, suggested by cell culture work from our group and others, also occurs in vivo, through specific effects on lysosomes. To me, as a practicing neurologist as well as a scientist, this suggests that developing TMEM106B as a therapeutic target in the thousands of people with FTD due to GRN mutations might be a reasonable approach.
Further, the paper pinpoints a potential interaction between TMEM106B and components of the vacuolar ATPase. While I would have liked to see a little more data in this area, this finding suggests a specific molecular mechanism for the altered lysosomal acidification seen by the authors and others (including our group) when TMEM106B expression levels are manipulated.
It is intriguing that only some of the phenotypes in the GRN null mouse are rescued by deletion of TMEM106B—and notably, the accumulation of lipofuscin and the microglial abnormalities seen in this animal model are not rescued. Despite this, the authors find rescue of retinal degeneration, which is promising from the standpoint of thinking about targeting TMEM106B to rescue neurodegeneration in people with FTD due to GRN mutations.View all comments by Alice Chen-Plotkin
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