These include: axonal transport failure, neurotrophic factor deprivation, toxic pro-neurotrophins, activation of intrinsic and extrinsic apoptotic signals, mitochondrial dysfunction, excitotoxic damage, oxidative stress, misbehaving reactive glia and loss of synaptic connectivity.
This transport failure leads to formation of axonal swellings, which are the physical manifestation of accumulation of axonal cargoes.
Interestingly, reduced microtubule acetylation and intracellular transport failure are regarded as early pathogenic events in the progression of Alzheimer's disease [10], [11].
However, since only certain neuronal populations appear vulnerable to ena down-regulation we favor the idea that specific cargoes are affected as opposed to a general transport failure, highlighting the exquisite regulation over motor proteins and their cargos.
Our data is consistent with the notion that reduced ENA levels impair the efficient flow of crucial cargoes to the synaptic terminals altering proper neuronal function, in turn leading to cell death (Figs. 5 7); a fast axonal anterograde transport failure, likely mediated by ENA-kinesin 1 interactions [40], could mediate this effect.
We next sought to identify the spatial distribution of axonal transport failure.
As such, it is important to ascertain whether the ONH is an important site of axonal transport failure in rodents.
In glaucoma, the lamina cribrosa of the ONH has long been considered a likely site of axonal transport failure.
In PD, type-I PM failure is characterized by progressive peritoneal thickening, inflammation, angiogenesis, and lymphangiogenesis, which ends in severe peritoneal fibrosis and peritoneal transport failure of water and solutes, shortening PM usefulness [ 24, 28].
