A Missense Mutation in the Coiled-Coil Domain of the KIF5A Gene and Late-Onset Hereditary Spastic Paraplegia

Giudice, Mariangela Lo; Neri, Marcella; Falco, Michele; Sturnio, Maurizio; Calzolari, Elisa; Benedetto, Daniela; Fichera, Marco

doi:10.1001/archneur.63.2.284

Cited by 48 publications

(50 citation statements)

References 15 publications

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“…The importance of intracellular transport is highlighted by the fact that mutations to these motors lead to genetic diseases such as amyotrophic lateral sclerosis [1], parapalegia [2], and Griscelli syndrome type 1 [3]. Molecular motors that drive cargo transport along the cytoskeletal highway include myosins traveling along actin filaments and kinesin and cytoplasmic dynein motors traveling on microtubules ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Cargo transport: molecular motors navigate a complex cytoskeleton

Ross¹,

Ali²,

Warshaw³

2008

Current Opinion in Cell Biology

304

265

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SummaryIntracellular cargo transport requires microtubule-based motors, kinesin and cytoplasmic dynein, and the actin-based myosin motors to maneuver through the challenges presented by the filamentous meshwork that comprises the cytoskeleton. Recent in vitro single molecule biophysical studies have begun to explore this process by characterizing what occurs as these tiny molecular motors happen upon an intersection between two cytoskeletal filaments. These studies, in combination with in vivo work, define the mechanism by which molecular motors exchange cargo while traveling between filamentous tracks and deliver it to its destination when going from the cell center to the periphery and back again.

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Section: Introductionmentioning

confidence: 99%

Cargo transport: molecular motors navigate a complex cytoskeleton

Ross¹,

Ali²,

Warshaw³

2008

Current Opinion in Cell Biology

304

265

View full text Add to dashboard Cite

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“…The importance of FAT on neuronal function and survival is demonstrated by the fact that partial loss-of-function mutations in either kinesin-1 (12) or CDyn subunits (13,14) result in late-onset degeneration of specific neuronal populations. Significantly, neuropathologies associated with mutations in molecular motors display a ''dying-back'' pattern of neurodegeneration (15,16) and adult onset of symptoms (17). Thus, alterations in either anterograde or retrograde FAT can suffice to produce a dying-back neuropathy (16,18,19).…”

mentioning

confidence: 99%

1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C

Morfini

Pigino

Opalach

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

117

110

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Parkinson's disease (PD), a late-onset condition characterized by dysfunction and loss of dopaminergic neurons in the substantia nigra, has both sporadic and neurotoxic forms. Neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its metabolite 1-methyl-4-phenylpyridinium (MPP؉) induce PD symptoms and recapitulate major pathological hallmarks of PD in human and animal models. Both sporadic and MPP؉-induced forms of PD proceed through a ''dying-back'' pattern of neuronal degeneration in affected neurons, characterized by early loss of synaptic terminals and axonopathy. However, axonal and synaptic-specific effects of MPP؉ are poorly understood. Using isolated squid axoplasm, we show that MPP؉ produces significant alterations in fast axonal transport (FAT) through activation of a caspase and a previously undescribed protein kinase C (PKC␦) isoform. Specifically, MPP؉ increased cytoplasmic dynein-dependent retrograde FAT and reduced kinesin-1-mediated anterograde FAT. Significantly, MPP؉ effects were independent of both nuclear activities and ATP production. Consistent with its effects on FAT, MPP؉ injection in presynaptic domains led to a dramatic reduction in the number of membranous profiles. Changes in availability of synaptic and neurotrophin-signaling components represent axonal and synaptic-specific effects of MPP؉ that would produce a dying-back pathology. Our results identify a critical neuronal process affected by MPP؉ and suggest that alterations in vesicle trafficking represent a primary event in PD pathogenesis. We propose that PD and other neurodegenerative diseases exhibiting dying-back neuropathology represent a previously undescribed category of neurological diseases characterized by dysfunction of vesicle transport and associated with the loss of synaptic function.is the second most common neurodegenerative disease after Alzheimer's disease with 1% of people Ͼ50 and 5% of those Ͼ85 developing PD (1). First described in 1817, PD is associated with a dying back of axons projecting from substantia nigra pars compacta (SNpC) to the striatum. When Ͼ80% of striatal dopaminergic synapses from nigral neurons no longer function, a shortage of dopamine in the striatum causes the movement defects that characterize PD (2). Although the proximate cause of PD is well understood, molecular pathogenesis in PD remained unknown. Approximately 95% of PD cases are sporadic, with an undetermined fraction resulting from environmental factors like 1-methyl-4-phenylpyridinium (MPTP) and other toxins (3). Ideally, treatments that prevent loss of affected neurons and maintain neuronal function will be developed, but this requires a better understanding of underlying molecular pathogenesis in PD (2).PD is unique among adult-onset neurodegenerative diseases in the existence of toxin-mediated forms of the disease that mirror the neuropathology observed in sporadic PD. MPTP and its metabolite 1-methyl-4-phenylpyridinium (MPPϩ) is the best-characterized example of a toxin-induced PD (4), although others such as p...

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“…one between coils 2 and 3 of the stalk, indicating that changes in Kif5A outside the head can cause HSP symptoms in humans (Lo Giudice et al 2006;Crimella et al 2011). Of particular interest in the head, a known human HSP allele, D73N (Schule et al 2008;Goizet et al 2009;Musumeci et al 2011), is identical to Drosophila Khc 74 (D79N), which causes an amino acid change in a-helix 1 (Figure 1, asterisks; Figure S2).…”

Section: Suppression Of Kinesin Mutations 175mentioning

confidence: 99%

“…To search for elements of the motor that are particularly important both for its functions in Drosophila and for human neurodegenerative disease, the locations of Khc missense changes were compared with those of Kif5A mutations linked to HSP and/or CMT2 (Reid et al 2002;Fichera et al 2004;Blair et al 2006;Lo Giudice et al 2006;Schule et al 2008;Tessa et al 2008;Goizet et al 2009;Crimella et al 2011;Musumeci et al 2011). The frequencies of changes in the three general structural regions of Khc are consistent with their evolutionary conservation ( Figure 1, Supporting Information, Figure S1); for Drosophila, 18 in the 350-amino-acid N-terminal head region, which is strongly conserved in all members of the kinesin family, and 4 in the less conserved 550 residue coiled-coil-forming neck and stalk region that homodimerizes Khc, links it to cargoes and may have some regulatory functions.…”

Section: Distribution Of Khc and Kif5a Mutationsmentioning

confidence: 99%

“…Of the 20 currently identified mutations, 18 are located in the N-terminal head region (Schule et al 2008;Goizet et al 2009). Full Kif5A sequencing has identified two in the coiled-coil-forming regions, one in the neck helix and one between coils 2 and 3 of the stalk, indicating that changes in Kif5A outside the head can cause HSP symptoms in humans (Lo Giudice et al 2006;Crimella et al 2011). Of particular interest in the head, a known human HSP allele, D73N (Schule et al 2008;Goizet et al 2009;Musumeci et al 2011), is identical to Drosophila Khc 74 (D79N), which causes an amino acid change in a-helix 1 (Figure 1, asterisks; Figure S2).…”

Section: Distribution Of Khc and Kif5a Mutationsmentioning

confidence: 99%

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Three Routes to Suppression of the Neurodegenerative Phenotypes Caused by Kinesin Heavy Chain Mutations

et al. 2012

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Kinesin-1 is a motor protein that moves stepwise along microtubules by employing dimerized kinesin heavy chain (Khc) subunits that alternate cycles of microtubule binding, conformational change, and ATP hydrolysis. Mutations in the Drosophila Khc gene are known to cause distal paralysis and lethality preceded by the occurrence of dystrophic axon terminals, reduced axonal transport, organelle-filled axonal swellings, and impaired action potential propagation. Mutations in the equivalent human gene, Kif5A, result in similar problems that cause hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth type 2 (CMT2) distal neuropathies. By comparing the phenotypes and the complementation behaviors of a large set of Khc missense alleles, including one that is identical to a human Kif5A HSP allele, we identified three routes to suppression of Khc phenotypes: nutrient restriction, genetic background manipulation, and a remarkable intramolecular complementation between mutations known or likely to cause reciprocal changes in the rate of microtubule-stimulated ADP release by kinesin-1. Our results reveal the value of large-scale complementation analysis for gaining insight into protein structure-function relationships in vivo and point to possible paths for suppressing symptoms of HSP and related distal neuropathies.T O transport organelles and other cargo complexes through cytoplasm over long distances, molecular motor proteins use paired, force-producing subunits to walk along microtubules. This is especially important for the development and maintenance of cells in which biosynthetic processes are asymmetrically located, such as neurons with long axons (Saxton and Hollenbeck 2012). Mutations in microtubule motor proteins are known to cause hereditary forms of spastic paraplegia (HSP) (Reid et al. 2002;Blackstone et al. 2011) and Charcot-Marie-Tooth type 2 (CMT2) (Goizet et al. 2009;Crimella et al. 2011) distal neuropathies and are suspected of contributing to the progression of other neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, Huntington's, and Parkinson's (De Vos et al. 2008;Morfini et al. 2009;Perlson et al. 2010). Defining the basic mechanisms of motor-driven cytoplasmic transport in axons and understanding how defects in them contribute to neurodegeneration are important areas for investigation.The structure and mechanochemistry of kinesin-1, a major axonal transport motor, have been the subject of intense study. The holoenzyme is centered around kinesin heavy chain (Khc, or Kif5 in humans), composed of an N-terminal globular head (the motor domain) connected to a long a-helical stalk that terminates in a small C-terminal globular tail (Vale et al. 1985;Yang et al. 1989). Two Khc heads, dimerized via coiled-coil interactions of their stalks, alternate cycles of ATP binding-hydrolysis-release and microtubule binding-release to move stepwise toward microtubule plus ends (reviewed by Vale and Milligan 2000;Sindelar 2011), which in axons are oriented away from the cell...

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A Missense Mutation in the Coiled-Coil Domain of the KIF5A Gene and Late-Onset Hereditary Spastic Paraplegia

Cited by 48 publications

References 15 publications

Cargo transport: molecular motors navigate a complex cytoskeleton

Cargo transport: molecular motors navigate a complex cytoskeleton

1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C

Three Routes to Suppression of the Neurodegenerative Phenotypes Caused by Kinesin Heavy Chain Mutations

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