Mark A. Smith

George Perry

Xiongwei Zhu

Abdelali Haoudi

Neurodegenerative Diseases: Mechanisms and Therapies

Recent evidence indicates that, alongside oxidative stress, dysregulation of the cell cycle in neurons susceptible to degeneration in Alzheimer disease may play a crucial role in the initiation of the disease. As such, the role of reproductive hormones, which are closely associated with the cell cycle both during development and after birth, may be of key import. While estrogen has been the primary focus, the protective effects of hormone replacement therapy on cognition and dementia only during a crucial period led us to expand the study of hormonal influences to other members of the hypothalamic pituitary axis. Specifically, in this review, we focus on luteinizing hormone, which is not only increased in the sera of patients with Alzheimer disease but, like estrogen, is modulated by hormone replacement therapy and also influences cognitive behavior and pathogenic processing in animal models of the disease. Targeting gonadotropins may be a useful treatment strategy for disease targeting multiple pleiotropic downstream consequences.

Gemma Casadesus

Emma Ramiro Puig

Kate M. Webber

Craig S. Atwood

Margarida Castell Escuer

Richard L. Bowen

Targeting Gonadotropins: An Alternative Option for Alzheimer Disease Treatment

Pesticides are routinely screened in studies that follow specificguidelines for possible neuropathogenicity in laboratory animals.These tests will detect chemicals that are by themselves stronginducers of neuropathogenesis if the tested strain is susceptiblerelative to the time of administration and methodology ofassessment. Organophosphate induced delayed neuropathy (OPIDN) isthe only known human neurodegenerative disease associated withpesticides and the existing study guidelines with hens are astandard for predicting the potential for organophosphates tocause OPIDN. Although recent data have led to the suggestion thatpesticides may be risk factors for Parkinsonism syndrome, thereare no specific protocols to evaluate this syndrome in theexisting study guidelines. Ideally additional animal models forhuman neurodegenerative diseases need to be developed andincorporated into the guidelines to further assure the public thatlimited exposure to pesticides is not a risk factor forneurodegenerative diseases.

John D. Doherty

Screening Pesticides for Neuropathogenicity

Alzheimer's disease is the principal cause of dementia throughout
the world and the fourth cause of death in developed
economies.This brain disorder is characterized by the formation of
brain protein aggregates, namely, the paired helical filaments and
senile plaques. Oxidative stress during life, neuroinflamamtion,
and alterations in neuron-glia interaction patterns have been also
involved in the etiopathogenesis of this disease. In recent years,
cumulative evidence has been gained on the involvement of
alteration in neuronal lipoproteins activity, as well as on the
role of cholesterol and other lipids in the pathogenesis of this
neurodegenerative disorder. In this review, we analyze the links
between changes in cholesterol homeostasis, and the changes of
lipids of major importance for neuronal activity and
Alheimer's disease. The investigation on the fine molecular
mechanisms underlying the lipids influence in the etiopathogenesis
of Alzheimer's disease may shed light into its treatment and
medical management.

Leonel Rojo

Marcela K. Sjöberg

Paula Hernández

Cristian Zambrano

Ricardo B. Maccioni

Roles of Cholesterol and Lipids in the Etiopathogenesis of
Alzheimer's Disease

Mechanisms that cause Alzheimer&#x2019;s disease (AD), an invariably
fatal neurodegenerative disease, are unknown. Important recent
data indicate that neuronal heme deficiency may
contribute to AD pathogenesis. If true, factors that contribute to
the intracellular heme deficiency could potentially alter the
course of AD. The porphyrias are metabolic disorders characterized
by enzyme deficiencies in the heme biosynthetic pathway. We
hypothesize that AD may differ significantly in individuals
possessing the genetic trait for an acute hepatic porphyria.  We
elaborate on this hypothesis and briefly review the
characteristics of the acute hepatic porphyrias that may be
relevant to AD. We note the proximity of genes encoding enzymes of
the heme biosynthesis pathway to genetic loci linked to sporadic,
late-onset AD. In addition, we suggest that identification of
individuals carrying the genetic trait for acute porphyria may
provide a unique resource for investigating AD pathogenesis and
inform treatment and management decisions.

Barney E. Dwyer

Meghan L. Stone

Heme Deficiency in Alzheimer&#x2019;s Disease: A Possible  Connection to
Porphyria

Parkinson's disease (PD) is a common age-related neurodegenerative disorder thought to result from the integrated effects of genetic background and exposure to neuronal toxins. Certain individual nuclear-encoded mitochondrial complex I gene polymorphisms were found to be associated with <mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>∼</mml:mo></mml:math><mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>2</mml:mn></mml:math>-fold risk variation in an Australian case-control sample. We further characterized this sample of <mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>306</mml:mn></mml:math> cases and <mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>321</mml:mn></mml:math> controls to determine the mutual information contained in the <mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>22</mml:mn></mml:math> SNPs and, additionally, level of pesticide exposure: five distinct risk sets were identified using grade-of-membership analysis. Of these, one was robust to pesticide exposure (I), three were vulnerable (II, III, IV), and another (V) denoted low risk for unexposed persons. Risk for individual subjects varied <mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>&gt;</mml:mo><mml:mn>16</mml:mn></mml:math>-fold according to level of membership in the vulnerable groups. We conclude that inherited variation in mitochondrial complex I genes and pesticide exposure together modulate risk for PD.

Elizabeth H. Corder

George D. Mellick

Parkinson's Disease in Relation to Pesticide Exposure and Nuclear Encoded Mitochondrial Complex I Gene Variants

Several recent observations suggest a connection between Gaucher
disease, the inherited deficiency of glucocerebrosidase, and the
synucleinopathies. Rare patients have been observed who develop
both Gaucher disease and parkinsonism. Autopsy studies on these
subjects reveal synuclein-positive Lewy bodies and inclusions. An
increased incidence of synucleinopathies also has been noted in
relatives of Gaucher probands. In complementary studies, screening
of patients with parkinsonism has identified a greater than
expected frequency of glucocerebrosidase mutations. These
glucocerebrosidase mutation carriers have a wide spectrum of
associated parkinsonian phenotypes, ranging from classic
L-dopa-responsive Parkinson disease to a phenotype
more characteristic of Lewy body dementia. Despite this
association, the vast majority of Gaucher carriers and patients
with Gaucher disease never develop parkinsonism. However,
mutations in this gene are likely to be a contributing risk factor
in subjects otherwise prone to developing synucleinopathies.

Kathleen S. Hruska

Ozlem Goker-Alpan

Ellen Sidransky

Gaucher Disease and the Synucleinopathies

Since 1999, oxidative damage to RNA molecules has been described
in several neurological diseases including Alzheimer's
disease, Parkinson's disease, Down syndrome, dementia
with Lewy bodies, prion disease, subacute sclerosing
panencephalitis, and xeroderma pigmentosum. An early involvement
of RNA oxidation of vulnerable neuronal population in the
neurodegenerative diseases has been demonstrated, which is
strongly supported by a recent observation of increased RNA
oxidation in brains of subjects with mild cognitive impairment.
Until recently, little is known about consequences and cellular
handling of the RNA damage. However, increasing body of evidence
suggests detrimental effects of the RNA damage in protein
synthesis and the existence of several coping mechanisms including
direct repair and avoiding the incorporation of the damaged
ribonucleotides into translational machinery. Further
investigations toward understanding of the consequences and
cellular handling mechanisms of the oxidative RNA damage may
provide significant insights into the pathogenesis and therapeutic
strategies of the neurodegenerative diseases.

Akihiko Nunomura

Kazuhiro Honda

Atsushi Takeda

Keisuke Hirai

Oxidative Damage to RNA in Neurodegenerative Diseases

Aggregated misfolded proteins are hallmarks of most neurodegenerative diseases. In a chronic disease state, including pathologic situations of oxidative stress, these proteins are sequestered into inclusions. Accumulation of aggregated proteins can be prevented by chaperones, or by targeting their degradation to the UPS. If the accumulation of these proteins exceeds their degradation, they may impair the function of the proteasome. Alternatively, the function of the proteasome may be preserved by directing aggregated proteins to the autophagy-lysosome pathway for degradation. Sequestosome 1/p62 has recently been shown to interact with polyubiquitinated proteins through its UBA domain and may direct proteins to either the UPS or autophagosome. P62 is present in neuronal inclusions of individuals with Alzheimer&#x27;s disease and other neurodegenerative diseases. Herein, we review p62&#x27;s role in signaling, aggregation, and inclusion formation, and specifically as a possible contributor to Alzheimer&#x27;s disease. The use of p62 as a potential target for the development of therapeutics and as a disease biomarker is also discussed.

Marie W. Wooten

Xiao Hu

J. Ramesh Babu

M. Lamar Seibenhener

Thangiah Geetha

Michael G. Paine

Michael C. Wooten

Signaling, Polyubiquitination, Trafficking, and Inclusions: Sequestosome 1/p62&#x27;s Role in Neurodegenerative Disease

<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>-synuclein is a key molecule in the pathogenesis of synucleinopathy including Parkinson&#39;s disease and multiple system atrophy. In this mini-review, we mainly focus on recent data obtained from cellular models of synucleinopathy and discuss the possible mechanisms of neurodegeneration. Recent progress suggests that the aggregate formation of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>-synuclein is cytoprotective and that its precursor oligomer (protofibril) may be cytotoxic. The catechol-derived quinones are the candidate molecules that facilitate the oligomer formation of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>-synuclein. Furthermore, the cellular membranes are shown to be the primary targets injured by mutant <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>-synucleins, and the mitochondrial dysfunction seems to be an initial step in the neuronal death.

Atsushi  Takeda

Takafumi  Hasegawa

Michiko  Matsuzaki-Kobayashi

Naoto  Sugeno

Akio  Kikuchi

Yasuto  Itoyama

Katsutoshi  Furukawa

Mechanisms of Neuronal Death in Synucleinopathy

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Neurodegenerative Diseases: Mechanisms and Therapies

Neurodegenerative Diseases: Mechanisms and Therapies

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