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Miro1 deficiency in amyotrophic lateral sclerosis.

Zhang F, Wang W, Siedlak SL, Liu Y, Liu J, Jiang K, Perry G, Zhu X, Wang X - Front Aging Neurosci (2015)

Bottom Line: Miro1, a RhoGTPase also referred to as Rhot1, is a key regulator of mitochondrial movement linking mitochondria and motor proteins.Glutamate excitotoxicity is one of the major pathophysiological mechanisms implicated in the pathogenesis of ALS, and we found that excessive glutamate challenge lead to significant reduction of Miro1 expression in spinal cord motor neurons both in vitro and in mice.Taken together, these findings show Miro1 deficiency in ALS patients and ALS animal models and suggest glutamate excitotoxicity as a likely cause of Miro1 deficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University Cleveland, OH, USA ; Department of Neurosurgery, Shandong Provincial Hospital, Shandong University Jinan, China.

ABSTRACT
Proper transportation of mitochondria to sites with high energy demands is critical for neuronal function and survival. Impaired mitochondrial movement has been repeatedly reported in motor neurons of amyotrophic lateral sclerosis (ALS) patients and indicated as an important mechanism contributing to motor neuron degeneration in ALS. Miro1, a RhoGTPase also referred to as Rhot1, is a key regulator of mitochondrial movement linking mitochondria and motor proteins. In this study, we investigated whether the expression of Miro1 was altered in ALS patients and ALS animal models. Immunoblot analysis revealed that Miro1 was significantly reduced in the spinal cord tissue of ALS patients. Consistently, the decreased expression of Miro1 was also noted only in the spinal cord, and not in the brain tissue of transgenic mice expressing ALS-associated SOD1 G93A or TDP-43 M337V. Glutamate excitotoxicity is one of the major pathophysiological mechanisms implicated in the pathogenesis of ALS, and we found that excessive glutamate challenge lead to significant reduction of Miro1 expression in spinal cord motor neurons both in vitro and in mice. Taken together, these findings show Miro1 deficiency in ALS patients and ALS animal models and suggest glutamate excitotoxicity as a likely cause of Miro1 deficiency.

No MeSH data available.


Related in: MedlinePlus

Expression of Miro1 in spinal cords of ALS patients. (A) Representative immunoblot and quantification analysis of Miro1 expression in thoracic spinal cord tissues from sporadic ALS (sALS) patients (n = 8) and age-matched control subjects (n = 6). Equal protein amounts (10 μg) were loaded and confirmed by GAPDH. VDAC1 was used as a mitochondrial specific marker. (B) Representative immunocytochemistry of mitochondrial marker COXI in lumbar spinal cords of sALS patients and age-matched control subjects. Arrowheads denote representative COX1 staining in motor neurons. Data are means ± sem. Statistics: student t test. **p < 0.01, compared with control subjects.
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Figure 1: Expression of Miro1 in spinal cords of ALS patients. (A) Representative immunoblot and quantification analysis of Miro1 expression in thoracic spinal cord tissues from sporadic ALS (sALS) patients (n = 8) and age-matched control subjects (n = 6). Equal protein amounts (10 μg) were loaded and confirmed by GAPDH. VDAC1 was used as a mitochondrial specific marker. (B) Representative immunocytochemistry of mitochondrial marker COXI in lumbar spinal cords of sALS patients and age-matched control subjects. Arrowheads denote representative COX1 staining in motor neurons. Data are means ± sem. Statistics: student t test. **p < 0.01, compared with control subjects.

Mentions: We first investigated the expression of Miro1 in spinal cord tissues from 8 ALS patients and 6 age-matched normal subjects. Immunoblot analysis revealed that Miro1 protein levels were dramatically reduced in ALS spinal cords compared to age-matched control spinal cords (Figure 1A). No significant changes in overall mitochondrial content were noted between ALS and control samples as evidenced by the constant expression levels of the mitochondrial marker VDAC1 (Figure 1A). We further performed immunocytochemical analysis of mitochondrial distribution in motor neurons using a specific antibody against mitochondrial marker, cytochrome c oxidase subunit 1 (COX-1). Consistent with the previous study showing impaired mitochondrial transport in ALS (Sasaki and Iwata, 1996), COX-1 immunoreactive mitochondria were only present in soma and depleted in the neurites of spinal cord motor neurons of ALS patients, compared to the uniform distribution of Cox-1 throughout the soma and neurites of age-matched control motor neurons (Figure 1B).


Miro1 deficiency in amyotrophic lateral sclerosis.

Zhang F, Wang W, Siedlak SL, Liu Y, Liu J, Jiang K, Perry G, Zhu X, Wang X - Front Aging Neurosci (2015)

Expression of Miro1 in spinal cords of ALS patients. (A) Representative immunoblot and quantification analysis of Miro1 expression in thoracic spinal cord tissues from sporadic ALS (sALS) patients (n = 8) and age-matched control subjects (n = 6). Equal protein amounts (10 μg) were loaded and confirmed by GAPDH. VDAC1 was used as a mitochondrial specific marker. (B) Representative immunocytochemistry of mitochondrial marker COXI in lumbar spinal cords of sALS patients and age-matched control subjects. Arrowheads denote representative COX1 staining in motor neurons. Data are means ± sem. Statistics: student t test. **p < 0.01, compared with control subjects.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4443026&req=5

Figure 1: Expression of Miro1 in spinal cords of ALS patients. (A) Representative immunoblot and quantification analysis of Miro1 expression in thoracic spinal cord tissues from sporadic ALS (sALS) patients (n = 8) and age-matched control subjects (n = 6). Equal protein amounts (10 μg) were loaded and confirmed by GAPDH. VDAC1 was used as a mitochondrial specific marker. (B) Representative immunocytochemistry of mitochondrial marker COXI in lumbar spinal cords of sALS patients and age-matched control subjects. Arrowheads denote representative COX1 staining in motor neurons. Data are means ± sem. Statistics: student t test. **p < 0.01, compared with control subjects.
Mentions: We first investigated the expression of Miro1 in spinal cord tissues from 8 ALS patients and 6 age-matched normal subjects. Immunoblot analysis revealed that Miro1 protein levels were dramatically reduced in ALS spinal cords compared to age-matched control spinal cords (Figure 1A). No significant changes in overall mitochondrial content were noted between ALS and control samples as evidenced by the constant expression levels of the mitochondrial marker VDAC1 (Figure 1A). We further performed immunocytochemical analysis of mitochondrial distribution in motor neurons using a specific antibody against mitochondrial marker, cytochrome c oxidase subunit 1 (COX-1). Consistent with the previous study showing impaired mitochondrial transport in ALS (Sasaki and Iwata, 1996), COX-1 immunoreactive mitochondria were only present in soma and depleted in the neurites of spinal cord motor neurons of ALS patients, compared to the uniform distribution of Cox-1 throughout the soma and neurites of age-matched control motor neurons (Figure 1B).

Bottom Line: Miro1, a RhoGTPase also referred to as Rhot1, is a key regulator of mitochondrial movement linking mitochondria and motor proteins.Glutamate excitotoxicity is one of the major pathophysiological mechanisms implicated in the pathogenesis of ALS, and we found that excessive glutamate challenge lead to significant reduction of Miro1 expression in spinal cord motor neurons both in vitro and in mice.Taken together, these findings show Miro1 deficiency in ALS patients and ALS animal models and suggest glutamate excitotoxicity as a likely cause of Miro1 deficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University Cleveland, OH, USA ; Department of Neurosurgery, Shandong Provincial Hospital, Shandong University Jinan, China.

ABSTRACT
Proper transportation of mitochondria to sites with high energy demands is critical for neuronal function and survival. Impaired mitochondrial movement has been repeatedly reported in motor neurons of amyotrophic lateral sclerosis (ALS) patients and indicated as an important mechanism contributing to motor neuron degeneration in ALS. Miro1, a RhoGTPase also referred to as Rhot1, is a key regulator of mitochondrial movement linking mitochondria and motor proteins. In this study, we investigated whether the expression of Miro1 was altered in ALS patients and ALS animal models. Immunoblot analysis revealed that Miro1 was significantly reduced in the spinal cord tissue of ALS patients. Consistently, the decreased expression of Miro1 was also noted only in the spinal cord, and not in the brain tissue of transgenic mice expressing ALS-associated SOD1 G93A or TDP-43 M337V. Glutamate excitotoxicity is one of the major pathophysiological mechanisms implicated in the pathogenesis of ALS, and we found that excessive glutamate challenge lead to significant reduction of Miro1 expression in spinal cord motor neurons both in vitro and in mice. Taken together, these findings show Miro1 deficiency in ALS patients and ALS animal models and suggest glutamate excitotoxicity as a likely cause of Miro1 deficiency.

No MeSH data available.


Related in: MedlinePlus