Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases

Abstract

Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a “dying back” pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND.

The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system

“…Subsequently, APP containing vesicles must be delivered at specific neuronal domains, a process that is mediated by phosphorylation‐dependent mechanisms that regulate the molecular motors (Morfini et al . , ; Brady & Morfini ). Interestingly, it has been reported that aberrant regulation of molecular motors by phosphorylation‐dependent mechanisms contributes to the loss of synaptic connectivity (Pigino et al .…”

“…; Deyts et al . ; Brady & Morfini ). In this context, targeting of APP at specific plasma membrane domains such as the GC relies on particular trafficking and sorting mechanisms characteristic of different population of neurons (Brunholz et al .…”

“…In this context, targeting of APP at specific plasma membrane domains such as the GC relies on particular trafficking and sorting mechanisms characteristic of different population of neurons (Brunholz et al . ; Brady & Morfini ). APP transits the secretory pathway and is enriched in highly plastic subcellular domains of the neuron such as the axonal GC.…”

Mechanisms of protein toxicity in neurodegenerative diseases

“…Furthermore, formation of ADF/cofilin-actin filament bundles (rods) that can occlude neurites and block vesicle transport has been implicated in neurodegenerative diseases [95]. In addition to these changes in cytoskeletal structures, accumulation of toxic disease proteins can lead to defects in axonal transport [96–101]. For example, defective axonal transport was reported to be a key early feature of pathogenesis prior to neurodegeneration in various SOD1 animal models of ALS [102–106].…”

Chlorpyrifos oxon promotes tubulin aggregation via isopeptide cross-linking between diethoxyphospho-Lys and Glu or Asp: Implications for neurotoxicity

“…Brady and co-workers (46, 47) have developed a unifying hypothesis to explain neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, and prion diseases as follows. 1) Aggregated proteins stimulate the activity of kinases.…”