A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease

Huisman, Evelien; Uylings, H.B.M.; Hoogland, Piet V.

doi:10.1002/mds.10713

Cited by 286 publications

(218 citation statements)

References 38 publications

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“…This further indicates that tg ␣-syn directly induced progressive motor decline and, additionally, that disease progression depends on continuous presence of transgene expression. However, the nonreversibility of symptoms in treated CaM_␣-syn mice suggested that neurodegeneration and nigral axon pathology was not ameliorated by a compensatory effect as increased neurogenesis, which might be a frequent response to injury in rodents (Arvidsson et al, 2002;Nakatomi et al, 2002;Zhao et al, 2003;Winner et al, 2006) and human brain (Huisman et al, 2004). Analysis of neurogenesis of 6-month-old CaM_␣-syn mice consistently revealed a negative impact on progenitor cells in the granular cell layer of the dentate gyrus.…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Nuber¹,

Petrasch‐Parwez²,

Winner³

et al. 2008

J. Neurosci.

165

134

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␣-Synuclein (␣-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether ␣-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type ␣-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting ␣-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, ␣-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.

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Section: Discussionmentioning

confidence: 99%

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Nuber¹,

Petrasch‐Parwez²,

Winner³

et al. 2008

J. Neurosci.

165

134

View full text Add to dashboard Cite

show abstract

“…The pathological substrate for this olfactory loss is not clear, some studies reporting conflicting information about damage to the olfactory epithelium or changes in olfactory bulb volumes as potential sources of these deficits (Muller et al, 2005;Witt et al, 2009;Wang et al, 2011). However, various studies have now reported an increase in the total number of periglomerular dopaminergic cells in the olfactory bulb of parkinsonian patients (Huisman et al, 2004;Morley and Duda, 2010).…”

Section: Early Anosmiamentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…Comparable observations have been made in patients with PD, with a decrease in mitotic cells in both the SVZ and hippocampus (the dentate gyrus subgranular zone being the second major area for adult neurogenesis) [91]. Moreover, an increase in dopaminergic olfactory neurons has been described in PD patients, despite their early and progressive loss in the sense of smell [92].…”

Section: Lrrk2 and Neurogenesismentioning

confidence: 96%

Update on the Functional Biology of Lrrk2

Melrose

2008

Future Neurol.

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The etiology of Parkinson's disease (PD) was long thought to be due to environmental factors. Following the discovery of autosomal-dominant mutations in the α-synuclein gene, and later recessive mutations in the DJ-1, Parkin and PINK-1 genes, the field of PD genetics exploded. In 2004, it was discovered that mutations in the PARK8 locus -leucine-rich repeat kinase 2 (LRRK2, Lrrk2) -are the most important genetic cause of autosomal-dominant PD. Lrrk2 substitutions also account for sporadic PD in certain ethnic populations and have been shown to increase the risk of PD in Asian populations. Drug therapies targeting Lrrk2 activity may therefore be beneficial to both familial and sporadic PD patients, hence understanding the role of Lrrk2 in health and disease is critical. This review aims to highlight the research effort concentrated on elucidating the functional biological role of Lrrk2, and to provide some future therapeutic perspectives.

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A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease

Cited by 286 publications

References 38 publications

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Update on the Functional Biology of Lrrk2

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