Motor Neuron Disease

Brooks, Benjamin Rix; DePaul, Roxanne; Tan, Yan De; Sanjak, Mohammed; Sufit, Robert; Robbins, JoAnne

doi:10.1007/978-1-4613-1495-0_18

Cited by 9 publications

(4 citation statements)

References 40 publications

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“…Neurodegeneration starts locally and spreads from one myotome segment to the segment next to it (53)(54)(55). This domino-like propagation of the pathology has previously been taken as evidence for a viral infection accompanying the disease (56).…”

Section: Discussionmentioning

confidence: 99%

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

Lindberg

Tibell

Oliveberg

2002

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

183

177

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More than 100 point mutations of the superoxide scavenger Cu͞Zn superoxide dismutase (SOD; EC 1.15.1.1) have been associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, these mutations are scattered throughout the protein and provide no clear functional or structural clues to the underlying disease mechanism. Therefore, we undertook to look for foldingrelated defects by comparing the unfolding behavior of five ALS-associated mutants with distinct structural characteristics: A4V at the interface between the N and C termini, C6F in the hydrophobic core, D90A at the protein surface, and G93A and G93C, which decrease backbone flexibility. With the exception of the disruptive replacements A4V and C6F, the mutations only marginally affect the stability of the native protein, yet all mutants share a pronounced destabilization of the metal-free apo state: the higher the stability loss, the lower the mean survival time for ALS patients carrying the mutation. Thus organism-level pathology may be directly related to the properties of the immature state of a protein rather than to those of the native species.A myotrophic lateral sclerosis (ALS) is a motor neuron syndrome where a sub group of 3-6% has been associated with a diverse set of mutations in the superoxide scavenger Cu͞Zn superoxide dismutase (SOD; 1.15.1.1) (1, 2). Interestingly, several of these mutations show perfectly native-like in vivo activity (3, 4) and metal coordination (5). As an alternative cause of disease, transgenic mouse models suggest that ALS arises through an adverse, and yet-unidentified, side reaction of the mutated protein causing cytotoxicity. Mice devoid of SOD retain normal motor function (6), as do mice overexpressing wild-type SOD. In contrast, mice expressing high levels of mutant human SOD in addition to endogenous SOD show neural damage. The collective evidence suggests that mutant SOD has gained a cytopathogenic function (7,8). Models for how the neurodegenerating toxicity arise include the following: (i) enzymatic side-reactions in catalytically promiscuous SOD mutants producing increased levels of oxidative compounds such as hydroxyl radicals (9-11) and peroxynitrite (12), (ii) release of free Cu ions (13), (iii) aberrant binding of SOD to other proteins (14), (iv) binding of mutant SOD to heat shock proteins (15, 16) with the subsequent prevention of their antiapoptotic function (16), (v) altered redox regulation (17), and (vi) formation of toxic SOD aggregates (18)(19)(20). Evidence that could potentially distinguish between these models was recently provided from mice lacking the metal-loading chaperone CCS (copper chaperone for SOD; ref. 21). The chaperone is essential for incorporating the copper ion and, hence, to gain the native protein. When the CCS gene was ablated, the ALS-associated mutations were observed to still provoke the disease, indicating that a copper-free precursor state of SOD causes neurotoxicity (21). Along this line, a broad spectrum of mechanistic scenarios is implicated...

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Section: Discussionmentioning

confidence: 99%

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

Lindberg

Tibell

Oliveberg

2002

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

183

177

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“…18 The difference in innervation between the SCM and the tongue may explain the different EMG sensitivities for these two muscles. With rostral progression of LMN degeneration, the upper cervical cord will be involved before the medulla, 3 and needle EMG abnormalities will occur in the SCM before the tongue. This would explain why in limb-onset ALS patients with no bulbar symptoms, EMG studies of the SCM were more often abnormal than examination of the tongue.…”

Section: Discussionmentioning

confidence: 99%

Electromyography of sternocleidomastoid muscle in ALS: A prospective study

Petajan

Smith

et al. 2002

Muscle and Nerve

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Needle electromyography (EMG) of the tongue is difficult to perform because of frequent uncontrollable movement. We chose the sternocleidomastoid (SCM) muscle as a possible alternative for assessing the involvement of the rostral neuraxis in amyotrophic lateral sclerosis (ALS). We prospectively studied 21 ALS patients during our initial diagnostic evaluation. EMG parameters that we recorded included the presence of abnormal spontaneous activity, pattern of motor unit potential recruitment, and configuration of motor unit action potentials. For the six patients with bulbar-onset ALS, three had abnormalities in the SCM and three had abnormalities in the tongue. In contrast, for the 15 patients with limb-onset ALS, 9 had abnormalities in the SCM, and only 3 had abnormalities in the tongue. Our results demonstrate the utility of needle EMG of the SCM in the evaluation of ALS. EMG of the SCM carries a similar sensitivity as the tongue in ALS patients with bulbar symptoms, but is more sensitive than the tongue in patients without bulbar symptoms. SCM innervation includes the rostral cervical cord and brainstem, and EMG abnormalities in this muscle support a diffuse involvement, which is unique to ALS.

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“…The average age of speakers in the female group was 58.2 years (SD = 11.2, range = 48 -86). The age range of participants corresponded with that of a typical population affected by ALS (Brooks et al, 1991). All but 4 participants (N012, N016, N020, N023) grew up in English speaking Canada or the United States.…”

Section: Methods Participantsmentioning

confidence: 99%

The effect of speaking rate on velopharyngeal function in healthy speakers

Gauster¹,

Yunusova²,

Zajac³

2010

Clinical Linguistics & Phonetics

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This study investigated the effect of speaking rate on aerodynamic and acoustic measures of velopharyngeal (VP) function in 27 adult speakers (14 M, 13 F). The pressure-flow method (Warren & Dubois, 1964) was used to collect aerodynamic data of /m/ and /p/ segments in the word "hamper" and the utterances "Mama made some lemon jam" (MMJ) and "Buy Bobby a puppy" (BBP). A Nasometer was used to collect nasalance scores and nasalance distance for MMJ and BBP. Measures were collected under 4 speaking rate conditions (normal, fast, slow, and slowest). Results indicated that nasal airflow and VP orifice area were unaffected by speaking rate whereas intraoral pressure decreased as speaking rate slowed. Nasalance was greater for BBP at slow speaking rates and nasalance distance (MMJ -BBP) decreased at slow rates. The data was interpreted with respect to expectations set forward in the literature on normal and disordered speech motor control.ii "Curiosity has its own reason for existing" -Albert EinsteinTo everyone in my life who encouraged me to ask questions.iii ACKNOWLEDGEMENTS

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Motor Neuron Disease

Cited by 9 publications

References 40 publications

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

Electromyography of sternocleidomastoid muscle in ALS: A prospective study

The effect of speaking rate on velopharyngeal function in healthy speakers

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