.
= For example, recent articles usually refer to abnormal accumulations of cholesterol:
Microsc Res Tech. 2005 Aug 15;67(3-4):114-120 [Epub ahead of print]
Molecular pathology and pathogenesis of inclusion-body myositis.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern California
Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912.
ABSTRACT
We summarize the molecular phenotype, diagnostic criteria, and the newest advances
related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis
(s-IBM), a muscle disease usually of persons over age 50. On the basis of our
research, several processes seem to be important in relation to the still-speculative
pathogenesis: 1) increased transcription and accumulation of amyloid-b precursor
protein (AbPP), and accumulation of its proteolytic fragment Ab; 2) abnormal
accumulation of cholesterol, caveolin-1, and apolipoprotein E; 3) oxidative
stress; 4) accumulations of intramuscle fiber multiprotein aggregates; and 5)
evidence that unfolded/misfolded proteins participate in s-IBM pathogenesis.
Our basic hypothesis is that overexpression of AbPP within the aging muscle
fibers is an early upstream event causing a subsequent pathogenic cascade.
CONCLUSION
We have presented what we consider the most relevant findings related to the
pathogenesis of s-IBM. These have not yet provided a definitive cause and treatment,
but they have pointed to potentially exciting avenues for exploring treatment
approaches to benefiting s-IBM patients. Examples are identification of factors
that would: 1) decrease intramuscle fiber expressions of b- and g-secretases
which might lead to decreased production of intracellularly toxic oligomeric
Ab42; 2) detoxify free radicals or prevent their formation within muscle fibers;
3) prevent misfolding/unfolding of muscle-fiber proteins and/or enhance their
disposal; and 4) decrease protein aggregation.
Microsc. Res. Tech. 67:114-120, 2005. (c) 2005 Wiley-Liss, Inc. August, 2005
= J Neurol Sci. 2005 Mar 15;229-230(1):233-40. Epub 2004 Dec 16.
Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.
Koudinov AR, Koudinova NV. Neurobiology of Lipids, P.O. Box 1665, Rehovot 76100,
Israel; Russian Academy of Medical Sciences, Timoshenko St., 38-27, Moscow 121359,
Russia.
We previously showed that fine tuning of neural cholesterol dynamics is essential
for basic synapse function, plasticity and behavior. Significant experimental
evidence indicates that cholinergic function, ionotropic and metabotropic receptor
machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta
or Abeta) biochemistry, neural oxidative stress reactions, and other features
of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis.
This evidence suggest that (i) cholesterol homeostasis break is the unifying
primary cause of sporadic and familial Alzheimer's disease (AD), neuromuscular
diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease
and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks
across the spectrum of neurodegenerative diseases. Provided is evidence-based
explanation of why extremely rare (but scientifically popular) cases of AD associated
with mutations in amyloid beta protein precursor (APP) and presenilin (PS) genes,
are translated into the disorder via membrane cholesterol sensitivity of APP
processing by secretases and Abeta generation. The reciprocal effect of Abeta
on cholesterol synthesis, cellular uptake, efflux and esterification is summarized,
as well as the potential implication of such biological function for the compensatory
Abeta-assisted restoration of the synaptic long-term potentiation (LTP) and
resulting inability of tackling amyloid to cure AD. PMID: 15760645 [PubMed -
in process]
= J Child Neurol. 2003 Mar;18(3):185-90.
Unfolding story of inclusion-body myositis and myopathies: role of misfolded
proteins, amyloid-beta, cholesterol, and aging.
Askanas V, Engel WK. USC Neuromuscular Center, Department of Neurology, University
of Southern California Keck School of Medicine, Good Samaritan Hospital, Los
Angeles, CA 90017-1912, USA. askanas@hsc.usc.edu
Sporadic inclusion-body myositis and hereditary inclusion-body myopathies are
progressive muscle diseases leading to severe disability. We briefly summarize
their clinical pictures and pathologic diagnostic criteria and discuss the latest
advances in illuminating their pathogenic mechanism(s). We emphasize how different
etiologies might lead to the strikingly similar pathology and possibly similar
pathogenic cascade. On the basis of our research, several processes seem to
be important in relation to the still speculative pathogenesis, including (a)
increased transcription and accumulation of amyloid-beta precursor protein and
accumulation of its proteolytic fragment amyloid-beta; (b) abnormal accumulation
of components related to lipid metabolism, for example, cholesterol, accumulation
of which is possibly owing to its abnormal trafficking; (c) oxidative stress;
(d) accumulations of other Alzheimer's disease-related proteins; and (e) a milieu
of muscle cellular aging in which these changes occur. We discuss a potentially
very important role of unfolded and/or misfolded proteins as a possible mechanism
in the formations of the inclusion bodies and other abnormalities. Publication
Types: Lectures PMID: 12731644 [PubMed - indexed for MEDLINE]
= Curr Opin Neurol. 2002 Oct;15(5):525-31.
Inclusion-body myositis and myopathies: different etiologies, possibly similar
pathogenic mechanisms.
Askanas V, Engel WK. USC Neuromuscular Center, Department of Neurology, University
of Southern California Keck School of Medicine, Good Samaritan Hospital, Los
Angeles, California 90017, USA. askanas@hsc.usc.edu
PURPOSE OF REVIEW: Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion
body myopathies are progressive muscle diseases that lead to severe disability.
We discuss recent advances in illuminating their pathogenic mechanism(s). RECENT
FINDINGS: We emphasize how different etiologies might lead to the strikingly
similar pathology and possibly similar pathogenic cascade. Our basic hypothesis
is that over-expression of amyloid-beta precursor protein within aging muscle
fibers is an early upstream event causing the subsequent pathogenic cascade.
On the basis of our research, several processes seem to be important in relation
to the still speculative pathogenesis: (a) increased transcription and accumulation
of amyloid-beta precursor protein, and accumulation of its proteolytic fragment
Abeta; (b) accumulations of phosphorylated tau and other Alzheimer-related proteins;
(c) accumulation of cholesterol and low-density lipoprotein receptors, the cholesterol
accumulation possibly due to its abnormal trafficking; (d) oxidative stress;
and (e) a milieu of muscle cellular aging in which these changes occur. We discuss
unfolded and/or misfolded proteins as a possible mechanism in formation of the
inclusion bodies and their consequences. The remarkable pathologic similarities
between s-IBM muscle and Alzheimer disease brain are discussed. SUMMARY: Unfolding
knowledge of the various pathogenetic aspects of the s-IBMs and hereditary inclusion
body myopathies may lead to new therapeutic avenues. Publication Types: Review
Review, Tutorial PMID: 12351995 [PubMed - indexed for MEDLINE]
= Curr Rheumatol Rep. 2002 Oct;4(5):427-33.
Newest pathogenetic considerations in inclusion-body myositis: possible role
of amyloid-beta, cholesterol, relation to aging and to Alzheimer's disease.
Askanas V, Engel WK. University of Southern California Neuromuscular Center,
Good Samaritan Hospital, 637 South Lucas Avenue, Los Angeles, CA 90017-1912,
USA. askanas@hsc.usc.edu
This report summarizes clinical features and diagnostic criteria, and the newest
advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body
myositis. On the basis of the authors' research, several processes seem to be
important in relation to the still-speculative pathogenesis: increased transcription
and accumulation of amyloid-b precursor protein and accumulation of its proteolytic
fragment amyloid-b; abnormal accumulation of components related to lipid metabolism
(eg, low-density lipoprotein receptors and cholesterol; accumulation of cholesterol
is possibly caused by its abnormal trafficking); oxidative stress; accumulations
of other Alzheimer-related proteins including phosphorylated tau; a milieu of
muscle cellular aging in which these changes occur. The authors' basic hypothesis
is that overexpression of amyloid-b precursor protein within the aging muscle
fibers is an early upstream event causing the subsequent pathogenic cascade.
The remarkable pathologic similarities between inclusion-body myositis muscle
and Alzheimer's disease brain are discussed. Publication Types: Review Review,
Tutorial PMID: 12217248 [PubMed - indexed for MEDLINE]
= Neurology. 2002 Feb 12;58(3):438-45.
Three lipoprotein receptors and cholesterol in inclusion-body myositis muscle.
Jaworska-Wilczynska M, Wilczynski GM, Engel WK, Strickland DK, Weisgraber KH,
Askanas V. USC Neuromuscular Center, Department of Neurology, University of
Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S.
Lucas Ave., Los Angeles, CA 90017-1912, USA.
BACKGROUND: An important aspect of inclusion-body myositis (IBM) vacuolated
muscle fibers (VMF) is abnormal accumulation of amyloid-beta precursor protein
(AbetaPP) epitopes and its product, amyloid-beta (Abeta), and of phosphorylated
tau (p-tau) in the form of paired helical filaments. Lipoprotein receptors and
cholesterol are known to play an important role in AbetaPP processing, Abeta
production, and tau phosphorylation. METHODS: In 10 IBM and 22 control muscle
biopsies the authors immunolocalized low-density lipoprotein receptor (LDLR),
very low-density lipoprotein receptor (VLDLR), and low-density lipoprotein receptor-related
protein (LRP), and colocalized them with Abeta, p-tau, APOE, and free cholesterol.
RESULTS: In each biopsy, virtually all IBM VMF had strong LDLR-immunoreactive
inclusions, which colocalized with Abeta, APOE, p-tau, and free cholesterol.
VLDLR was increased mainly diffusely, but in approximately 50% of the VMF it
was also accumulated in the form of inclusions colocalizing with Abeta, APOE,
and free cholesterol, but not with p-tau. LRP inclusions were present in a few
VMF. In all myopathies, a subset of regenerating and necrotizing muscle fibers
had prominent diffuse accumulation of both LDLR and free cholesterol. At normal
neuromuscular junctions (NMJ) postsynaptically, LDLR and VLDLR, but not LRP,
were immunoreactive. CONCLUSIONS: 1) Abnormal accumulation of LDLR, VLDLR, LRP,
and cholesterol within IBM vacuolated muscle fibers suggests novel roles for
them in the IBM pathogenesis. 2) Expression of LDLR and VLDLR at normal NMJ
suggests physiologic roles for them in transsynaptic signaling pathways, increased
internalization of lipoproteins there, or both. 3) Increased LDLR and free cholesterol
in some regenerating and necrotizing muscle fibers suggest a role for them in
human muscle fiber growth and repair and necrotic death. PMID: 11839845 [PubMed
- indexed for MEDLINE]
= Curr Opin Neurol Neurosurg. 1992 Oct;5(5):645-54.
Inflammatory and toxic myopathies.
Dalakas MC. Neuromuscular Diseases Section, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
The major advances in the immunopathogenesis and treatment of inflammatory myopathies,
and the main criteria that distinguish polymyositis (PM) from dermatomyositis
(DM) or inclusion-body myositis (IBM) are presented. The origin and implications
of the amyloid and ubiquitin deposits found within the vacuolated fibers of
patients with IBM are considered. The pathogenesis of human immunodeficiency
virus (HIV) and human T-cell lymphotrophic virus (HTLV)-I-associated PM is presented,
and the role of retroviruses in triggering PM, even in the absence of detectable
viral genome within the muscle fibers, is discussed. In addition, three toxic
myopathies with distinct morphologic, biochemical, or molecular characteristics,
caused by zidovudine [azidothymidine (AZT) myopathy], the cholesterol-lowering-agent
myopathy (CLAM), and the combination of blocking agents with corticosteroids
are presented. Publication Types: Review Review, Tutorial PMID: 1327303 [PubMed
- indexed for MEDLINE]
.