Somatosensory function in asymptomatic <i>Parkin‐</i>mutation carriers

Gierthmühlen, Janne; Schumacher, Sonja; Deuschl, Günther; Fritzer, Elfriede; Klein, Christine; Baron, Ralf; Helmchen, C.

doi:10.1111/j.1468-1331.2009.02797.x

Cited by 14 publications

(8 citation statements)

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“…The importance of the ubiquitin system for controlling diverse features of neuronal function is well established ( Kowalski & Juo, 2012 ; Tai & Schuman, 2008 ). Recent studies have implicated the USS in controlling aspects of sensory system function in both C. elegans and other species ( Chen & Chalfie, 2015 ; Gierthmuhlen et al, 2010 ; James, Key & Beverdam, 2014 ; Kim et al, 2015 ; Lu et al, 2009 ; Sourisseau et al, 2001 ). The APC ubiquitin ligase is a known regulator of many of these processes, including neuronal survival, axon outgrowth and dendritogenesis, as well as synapse formation and signaling ( Kowalski et al, 2014 ; Puram & Bonni, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies also confirm the importance of the USS in controlling sensory processing or signal transduction and identify ubiquitin ligases involved in this regulation. Cold pain sensation and the function of specific central and afferent pain pathways were found to be reduced in Parkinson’s disease patients carrying mutations in the parkin E3 ligase ( Gierthmuhlen et al, 2010 ), suggesting important roles for the USS in controlling the signaling and/or connectivity of these neurons. Loss of function of the Ring finger ubiquitin ligase RNF170, mutation of which is linked with a rare autosomal-dominant sensory ataxia (ADSA) in humans, causes reduced proprioceptive sensitivity and thermal pain sensing in mice ( Kim et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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The Anaphase-Promoting Complex (APC) ubiquitin ligase affects chemosensory behavior inC. elegans

Jennings

Kowalski

2016

PeerJ

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The regulation of fundamental aspects of neurobiological function has been linked to the ubiquitin signaling system (USS), which regulates the degradation and activity of proteins and is catalyzed by E1, E2, and E3 enzymes. The Anaphase-Promoting Complex (APC) is a multi-subunit E3 ubiquitin ligase that controls diverse developmental and signaling processes in post-mitotic neurons; however, potential roles for the APC in sensory function have yet to be explored. In this study, we examined the effect of the APC ubiquitin ligase on chemosensation in Caenorhabditis elegans by testing chemotaxis to the volatile odorants, diacetyl, pyrazine, and isoamyl alcohol, to which wild-type worms are attracted. Animals with loss of function mutations in either of two alleles (g48 and ye143) of the gene encoding the APC subunit EMB-27 APC6 showed increased chemotaxis towards diacetyl and pyrazine, odorants sensed by AWA neurons, but exhibited normal chemotaxis to isoamyl alcohol, which is sensed by AWC neurons. The statistically significant increase in chemotaxis in the emb-27 APC6 mutants suggests that the APC inhibits AWA-mediated chemosensation in C. elegans. Increased chemotaxis to pyrazine was also seen with mutants lacking another essential APC subunit, MAT-2 APC1; however, mat-2 APC1 mutants exhibited wild type responses to diacetyl. The difference in responsiveness of these two APC subunit mutants may be due to differential strength of these hypomorphic alleles or may indicate the presence of functional sub-complexes of the APC at work in this process. These findings are the first evidence for APC-mediated regulation of chemosensation and lay the groundwork for further studies aimed at identifying the expression levels, function, and targets of the APC in specific sensory neurons. Because of the similarity between human and C. elegans nervous systems, the role of the APC in sensory neurons may also advance our understanding of human sensory function and disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Anaphase-Promoting Complex (APC) ubiquitin ligase affects chemosensory behavior inC. elegans

Jennings

Kowalski

2016

PeerJ

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“…Thus, neuropathic pain symptoms in Parkinson's disease are not associated with loss of sensory (or motor) function 22, 23. Similarly, decreases in sensory threshold (cold hyperalgesia) can be detected psychophysically in carriers of the Parkin mutation (which causes autosomal recessive juvenile Parkinsonism) even when detailed neurography reveals no deficit in nerve function 24. Indeed, when neurodegeneration ultimately does occur in advanced stages of Parkinson's disease it may be associated with loss of pain perception 17.…”

Section: Neuropathic Pain In Neurodegenerative Diseases Might Be Causmentioning

confidence: 99%

Pain and death: Neurodegenerative disease mechanisms in the nociceptor

Reichling

Levine

2011

Annals of Neurology

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Chronic peripheral neuropathic pain is the result of abnormal activity in sensory nerves. It is well recognized that this sensory nerve dysfunction can be caused by traumatic, toxic, or metabolic insult to the nerve. In addition, there is growing recognition that neuropathic pain is a frequent manifestation of neurodegenerative diseases. In this regard, important clues to the cellular mechanisms of neuropathic pain may be found by close examination of neurodegenerative diseases (including Parkinson's disease) in which neuropathic pain is often an underappreciated but important clinical manifestation. This approach identifies specific mitochondrial and cytoskeletal mechanisms, previously implicated in the pathophysiology of neurodegenerative diseases in the central nervous system, that might contribute to neuropathic dysfunction in peripheral sensory nerve fibers. Investigations in preclinical models of common peripheral neuropathic pain conditions have supported the idea that a subset of these cellular mechanisms of neurodegeneration can produce painful hyperactivity in primary afferent nociceptors. Importantly, this emerging concept of neurodegenerative disease mechanisms in the primary afferent nociceptor identifies novel molecular targets for the treatment neuropathic pain.

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“…Movement disorders, such as Parkinson’s disease (PD) and dystonia, are characterised not only by motor symptoms but also by somatosensory alterations [1]–[6]. For instance, patients with PD display a number of somatosensory deficits, including abnormal temporal [4], [7], [8] and spatial discrimination of sensory stimuli [2], [9] and altered proprioception [10]–[14].…”

Section: Introductionmentioning

confidence: 99%

Aristotle’s Illusion in Parkinson’s Disease: Evidence for Normal Interdigit Tactile Perception

et al. 2014

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Sensory alterations, a common feature of such movement disorders as Parkinson’s disease (PD) and dystonia, could emerge as epiphenomena of basal ganglia dysfunction. Recently, we found a selective reduction of tactile perception (Aristotle’s illusion, the illusory doubling sensation of one object when touched with crossed fingers) in the affected hand of patients with focal hand dystonia. This suggests that reduced tactile illusion might be a specific feature of this type of dystonia and could be due to abnormal somatosensory cortical activation. The aim of the current study was to investigate whether Aristotle’s illusion is reduced in the affected hand of patients with PD. We tested 15 PD patients, in whom motor symptoms were mainly localised to one side of the body, and 15 healthy controls. Three pairs of fingers were tested in crossed (evoking the illusion) or parallel position (not evoking the illusion). A sphere was placed in the contact point between the two fingers and the blindfolded participants had to say whether they felt one or two stimuli. Stimuli were applied on the affected and less or unaffected side of the PD patients. We found no difference in illusory perception between the PD patients and the controls, nor between the more affected and less/unaffected side, suggesting that Aristotle’s illusion is preserved in PD. The retained tactile illusion in PD and its reduction in focal hand dystonia suggest that the basal ganglia, which are dysfunctional in both PD and dystonia, may not be causally involved in this function. Instead, the level of activation between digits in the somatosensory cortex may be more directly involved. Finally, the similar percentage of illusion in the more affected and less or unaffected body sides indicates that the illusory perception is not influenced by the presence or amount of motor symptoms.

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Somatosensory function in asymptomatic Parkin‐mutation carriers

Abstract: Sensory abnormalities of asymptomatic Parkin-mutation carriers as obtained by QST suggest impairment of either small and large peripheral pathways or central somatosensory processing. In contrast to Parkin-associated PD, asymptomatic Parkin-mutation carriers do not show a reduced SNAP.

Cited by 14 publications

References 14 publications

The Anaphase-Promoting Complex (APC) ubiquitin ligase affects chemosensory behavior inC. elegans

The Anaphase-Promoting Complex (APC) ubiquitin ligase affects chemosensory behavior inC. elegans

Pain and death: Neurodegenerative disease mechanisms in the nociceptor

Aristotle’s Illusion in Parkinson’s Disease: Evidence for Normal Interdigit Tactile Perception

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