Conventional kinesin: Biochemical heterogeneity and functional implications in health and disease

Morfini, Gerardo; Schmidt, Nadine; Weissmann, Carina; Pigino, Gustavo; Kins, Stefan

doi:10.1016/j.brainresbull.2016.06.009

Cited by 55 publications

(53 citation statements)

References 104 publications

(130 reference statements)

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“…Thus, at least six different variants of conventional kinesin can be defined by their subunit composition (Fig.1B), although many more variants are predicted based on alternative splicing of KLC1, so the ultimate number of unique conventional kinesin motors is uncertain (Morfini et al, 2016) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…1). The functional significance of these conventional kinesin variants has not been fully established, but cumulative experimental evidence suggests a role in both the binding to selected MBO cargoes (Dahlström et al, 1991; Deboer et al, 2008; Elluru et al, 1995; Szodorai et al, 2009) and their delivery to discrete neuritic subcompartments (Morfini et al, 2016). The diversity of kinesin-1 motors, coupled with the wide variety of cargos and subcellular compartments in neurons, suggest that multiple regulatory pathways must exist to control the delivery of specific cargoes to selected subcellular domains (Brady, 1995; Brady and Sperry, 1995; Morfini et al, 2016; Morfini et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…While the specific MBO cargoes transported by kinesin-1A-containing variants of conventional kinesin have not been established, these observations suggest a unique dependence of upper motor neurons on the trafficking of cargoes powered by kinesin-1A-contaning variants of conventional kinesin. Alternatively, different kinesin-1 isoforms may be subject to cell type-specific regulatory mechanisms (Morfini et al, 2016). Finally, other kinesin family members may play a greater role in some neuronal populations than others (Hirokawa et al, 2010), but this possibility is less well documented.…”

Section: Introductionmentioning

confidence: 99%

“…Such delivery of selected components at specialized neuritic subdomains long implied the existence of targeting mechanisms (Brady, 1995; Elluru et al, 1995; Morfini et al, 2001). The realization that motor proteins are phosphorylated in vivo suggested that phosphorylation may represent a molecular basis for targeted delivery in neurons (Donelan et al, 2002; Hollenbeck, 1990; Hollenbeck, 1993; Morfini et al, 2004; Morfini et al, 2002), but the challenge was to identify relevant kinases involved in the regulation of AT (Morfini et al, 2016; Morfini et al, 2001). …”

Section: Introductionmentioning

confidence: 99%

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

Brady

Morfini

2017

Neurobiology of Disease

128

123

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Brady

Morfini

2017

Neurobiology of Disease

128

123

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“…Hyperphosphorylation of the microtubule-associated protein tau–a pathological hallmark of Alzheimer's disease (Iqbal et al, 2016)– promotes abnormal translocation and accumulation of tau in the soma and aberrant assembly of microtubules, driving axonal transport deficits and other neurodegenerative effects (Majid et al, 2014; Morfini et al, 2016). While tauopathy likely plays a mechanistic role in glaucoma, evidence of tau phosphorylation and translocation in a glaucoma model has only recently been uncovered (Chiasseu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma

Wilson¹,

Smith²,

Inman³

et al. 2016

Front. Neurosci.

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Axonal transport deficits precede structural loss in glaucoma and other neurodegenerations. Impairments in structural support, including modified cytoskeletal proteins, and microtubule-destabilizing elements, could be initiating factors in glaucoma pathogenesis. We investigated the time course of changes in protein levels and post-translational modifications in the DBA/2J mouse model of glaucoma. Using anterograde tract tracing of the retinal projection, we assessed major cytoskeletal and transported elements as a function of transport integrity in different stages of pathological progression. Using capillary-based electrophoresis, single- and multiplex immunosorbent assays, and immunofluorescence, we quantified hyperphosphorylated neurofilament-heavy chain, phosphorylated tau (ptau), calpain-mediated spectrin breakdown product (145/150 kDa), β–tubulin, and amyloid-β42 proteins based on age and transport outcome to the superior colliculus (SC; the main retinal target in mice). Phosphorylated neurofilament-heavy chain (pNF-H) was elevated within the optic nerve (ON) and SC of 8–10 month-old DBA/2J mice, but was not evident in the retina until 12–15 months, suggesting that cytoskeletal modifications first appear in the distal retinal projection. As expected, higher pNF-H levels in the SC and retina were correlated with axonal transport deficits. Elevations in hyperphosphorylated tau (ptau) occurred in ON and SC between 3 and 8 month of age while retinal ptau accumulations occurred at 12–15 months in DBA/2J mice. In vitro co-immunoprecipitation experiments suggested increased affinity of ptau for the retrograde motor complex protein dynactin. We observed a transport-related decrease of β-tubulin in ON of 10–12 month-old DBA/2J mice, suggesting destabilized microtubule array. Elevations in calpain-mediated spectrin breakdown product were seen in ON and SC at the earliest age examined, well before axonal transport loss is evident. Finally, transport-independent elevations of amyloid-β42, unlike pNF-H or ptau, occurred first in the retina of DBA/2J mice, and then progressed to SC. These data demonstrate distal-to-proximal progression of cytoskeletal modifications in the progression of glaucoma, with many of these changes occurring prior to complete loss of functional transport and axon degeneration. The earliest changes, such as elevated spectrin breakdown and amyloid-β levels, may make retinal ganglion cells susceptible to future stressors. As such, targeting modification of the axonal cytoskeleton in glaucoma may provide unique opportunities to slow disease progression.

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KIF16B is a candidate gene for a novel autosomal‐recessive intellectual disability syndrome

Alsahli

Arold

Alfares

et al. 2018

American J of Med Genetics Pt A

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Intellectual disability (ID) and global developmental delay are closely related; the latter is reserved for children under the age of 5 years as it is challenging to reliably assess clinical severity in this population. ID is a common condition, with up to 1%-3% of the population being affected and leading to a huge social and economic impact. ID is attributed to genetic abnormalities most of the time; however, the exact role of genetic involvement in ID is yet to be determined. Whole exome sequencing (WES) has gained popularity in the workup for ID, and multiple studies have been published examining the diagnostic yield in identification of the disease-causing variant (16%-55%), with the genetic involvement increasing as intelligence quotient decreases. WES has also accelerated novel disease gene discovery in this field. We identified a novel biallelic variant in the KIF16B gene (NM_024704.4:c.3611T > G) in two brothers that may be the cause of their phenotype.

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Conventional kinesin: Biochemical heterogeneity and functional implications in health and disease

Cited by 55 publications

References 104 publications

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

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

Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma

KIF16B is a candidate gene for a novel autosomal‐recessive intellectual disability syndrome

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