![]() ![]() Unlike in fibroblasts, Rab7 compartments in dendrites frequently lack LAMP1, are not acidified, and do not contain the abundant lysosomal proteases cathepsin (Cat) B or D. Second, we discovered that dendrites contain distinct Rab7 + compartments which we term “early” LEs and “late” LEs depending on whether LAMP1 is present or not. We discovered a steep spatial gradient of endosomes along dendrites: EEs and LEs are abundant throughout dendrites, whereas the abundance of degradative acidified lysosomes declines rapidly with increasing distance from the soma both ex vivo and in vivo. Using the same markers and functional assays routinely used in fibroblasts, we undertook a comprehensive categorization of endosomes in dendrites. In fact, the overlap of Rab7 with LAMP1 is so extensive in fibroblasts (>75% Humphries et al., 2011 Hubert et al., 2016) that LEs and lysosomes are often combined into a single “LE/lysosome” category. In fibroblasts, endosomal populations and their maturation are well studied, and several markers are routinely used to distinguish early endosomes (EEs EEA1) from late endosomes (LEs) and lysosomes (Rab7/LAMP1). We conclude that the majority of dendritic LAMP1 endosomes are not degradative lysosomes and that terminal degradation of dendritic cargos such as Nsg1, Nsg2, and DNER requires Rab7-dependent transport in LEs to somatic lysosomes. Second, Rab7 activity is required to mobilize distal predegradative LEs for transport to the soma and terminal degradation. Unlike in fibroblasts, we found that the majority of dendritic Rab7 late endosomes (LEs) do not contain LAMP1 and that a large proportion of LAMP1 compartments do not contain CatB/D. Early EEA1-positive and late Rab7-positive endosomes are found throughout dendrites, whereas the density of degradative LAMP1- and cathepsin (Cat) B/D–positive lysosomes decreases steeply past the proximal segment. We discovered a spatial heterogeneity of endolysosomal compartments in dendrites. We characterized the behavior of the short-lived dendritic membrane proteins Nsg1 and Nsg2 to determine whether these proteins are degraded locally in dendrites or centrally in the soma. Disturbances in proteostasis lead to aggregates and cellular stress. Neurons are large and long lived, creating high needs for regulating protein turnover.
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