Elsevier

Progress in Neurobiology

Volume 70, Issue 6, August 2003, Pages 473-507
Progress in Neurobiology

Patterned Purkinje cell death in the cerebellum

https://doi.org/10.1016/S0301-0082(03)00114-XGet rights and content

Abstract

The object of this review is to assemble much of the literature concerning Purkinje cell death in cerebellar pathology and to relate this to what is now known about the complex topography of the cerebellar cortex. A brief introduction to Purkinje cells, and their regionalization is provided, and then the data on Purkinje cell death in mouse models and, where appropriate, their human counterparts, have been arranged according to several broad categories—naturally-occurring and targeted mutations leading to Purkinje cell death, Purkinje cell death due to toxins, Purkinje cell death in ischemia, Purkinje cell death in infection and in inherited disorders, etc. The data reveal that cerebellar Purkinje cell death is much more topographically complex than is usually appreciated.

Introduction

The cerebellum is a convenient model in which to explore cell death for several reasons. First, the long developmental schedule—around 6 weeks in mice—makes the cerebellum particularly vulnerable to both developmental and environmental insults. Second, because the cerebellum is not crucial for life, cerebellar mutants tend not to be embryonically lethal, and therefore animal models can be examined as adults. Third, cerebellar abnormalities are usually straightforward to recognize: cerebellar damage manifests itself as motor coordination problems—oculomotor disturbances, dysarthia, limb movement deficits and abnormalities in gait and posture (Trouillas et al., 1997)—that are easily recognized both clinically and in animal holding facilities. As a result, numerous clinical syndromes are known with cerebellar involvement and many spontaneous mutations that affect cerebellar development and function have been recognized (for example, over 50 naturally-occurring “cerebellar” mutants have been identified in mice). As a result, patterned Purkinje cell death has been recognized in humans since at least 1905 (Thomas, 1905) and clearly in mice since the work of Wassef et al. (1987).

Section snippets

Cerebellar histology

The cerebellum is divided into the medial vermis and lateral extensions known as the hemispheres. Classically, the cerebellum is divided into the anterior, posterior and flocculonodular lobes as defined by the major fissures, and each lobe is further subdivided into lobules. The histology of the cerebellum as seen by using conventional methods appears rather uniform and cytoarchitectonic areas similar to those in the cerebral cortex are not present. The entire cerebellar cortex is formed of the

Purkinje cell development

The adult cerebellum in the mouse develops over a 6-week period between embryonic age (E)7 and postnatal age (P)30. Cerebellar development is dominated by the interplay between two germinal epithelia—the external granular layer, which produces the granule cells, and the ventricular zone of the fourth ventricle, which produces the Purkinje cells (reviewed in Goldowitz and Hamre, 1998, Wang and Zoghbi, 2001, etc.). The brief description that follows addresses only the Purkinje cells, and

Naturally-occurring mutations resulting in Purkinje cell death

Purkinje cell death manifests itself behaviorally as ataxia and tremor and gross pathological examination usually reveals an atrophic cerebellum. The first example of which we are aware comes from the description of an ataxic patient by Thomas (1905, Fig. 2). However, the appearance of the cerebellum after Purkinje cell death depends upon when death occurred, and whether or not the insult selectively affected a subpopulation of Purkinje cells. Death in the adult typically presents as gaps in

Spinocerebellar ataxias

Spinocerebellar ataxias are a heterogeneous group of inherited disorders with the prominent feature of cerebellar degeneration. Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant triplet repeat disorder characterized by the degeneration of Purkinje cells and a select population of brainstem neurons. Banfi et al. (1996) cloned and characterized the murine homolog of the human gene SCA1. Murine and human ataxin-1 are highly homologous, but the CAG repeat is virtually absent from the

Ibogaine

Ibogaine toxicity is a model of cerebellar excitotoxic Purkinje cell death. Ibogaine is a psychoactive indole alkoid extracted from the West African shrub Tabernanthe iboga, which is structurally similar to harmaline. The potential for ibogaine as an anti-addictive medication fuelled research into possible neurotoxic side effects. Acute effects of ibogaine injection include severe tremor, ataxia and hypotonia (Xu et al., 2000). Rats injected with low doses of ibogaine (10–40 mg/kg; Molinari et

Purkinje cell death due to ischemia

Global brain ischemia produces selective degeneration within the central nervous system. Purkinje cells are particularly sensitive. For example, in a rat model of cardiac arrest and resuscitation, over 60% of Purkinje cells was lost in 1 week following a 10 min arrest (Brasko et al., 1995). Hypoxic stress leads to a number of morphological abnormalities within Purkinje cells including cytoplasmic darkening, nuclear condensation, autolytic necrosis with cytoplasmic vacuoles, and smaller more

Purkinje cell death due to prion diseases

Prion diseases are transmissible neurodegenerative disorders also known as transmissible spongiform encephalopathies (TSE). In humans, these include Creutzfeldt–Jakob disease (CJD), Gerstmann–Straussler–Scheinker disease (GSS), fatal familial insomnia (FFI) and kuru. CJD can occur both sporadically or as a dominantly inherited disease. GSS and FFI both seem to be inherited while kuru was transmitted as a result of cannibalism. Veterinary TSEs include scrapie (in sheep) and bovine spongiform

Purkinje cell death due to Borna disease virus infection

Borna disease virus is a single-stranded non-cytolytic RNA virus that replicates within the central nervous system and causes acute and chronic neurological disease. Animals infected with Borna disease virus during neonatal development have profound cerebellar pathology (Bautista et al., 1995). Persistent infection results in cerebellar hypoplasia (Zocher et al., 2000) caused by apoptosis of both granule and Purkinje cells (Hornig et al., 1999, Weissenbock et al., 2000, Zocher et al., 2000). It

Purkinje cell death due to traumatic brain injury

Traumatic brain injury (TBI) is a common health issue and presents significant morbidity and mortality. TBIs can be classified in terms of primary and secondary damage or in terms of focal versus diffuse damage. Purkinje cells have been shown to be particularly sensitive to trauma in many experimental paradigms. Fluid percussive impact to the forebrain serves as a model for mild TBI. Examination of the cerebellum 7 days post-injury revealed significant microglial activation within the

Purkinje cell death due to chronic epilepsy or status epilepticus

Epilepsy is one of the most common neurological disorders, characterized by a tendency for recurrent seizures and can result in neuronal loss. One of the central dilemmas in elucidating the pathophysiology of epileptic seizures is distinguishing between the causative lesion and secondary lesions produced by chronic seizures. In addition, when ascribing neuronal degeneration to seizure activity, coexisting conditions such as hypotension, hypoxemia, hypoglycemia or hypothermia, must be excluded (

Purkinje cell death due to chronic rhizomelic chondrodysplasia punctata

Chronic rhizomelic chondrodysplasia punctata is an autosomal recessive peroxisomal disorder caused by disruption of the PEX7 gene (Braverman et al., 1997, Motley et al., 1997, Purdue et al., 1997), which codes for the peroxisomal targeting signal-2 receptor. It is characterized by proximal limb shortening, cataracts and severe mental retardation. Agamanolis and Novak (1995) were the first to report cerebellar atrophy in a 3-year-old patient. Powers et al. (1999) went on to characterize the

Purkinje cell death due to mitochondrial disorders

Mitochondrial disorders are classified based on defects in the mitochondrial genome, abnormalities in nuclear–mitochondrial cross-talk and defects in oxidative phosphorylation genes encoded by the nuclear genome (reviewed in Zeviani et al., 2002). A common feature of many mitochondrial diseases is cerebellar ataxia.

Purkinje cell loss in autism

Autism is a pervasive developmental disorder characterized by social, linguistic and sensorimotor deficits. Cerebellar abnormalities are thought to contribute to the pathophysiology of autism. Most studies involve measurements of cerebellar cross-sectional area from MRI scans. The results are conflicting. Courchesne et al. (1994) found that while majority of subjects had cerebellar hypoplasia, some were hyperplasic. The posterior lobe is suggested to be preferentially hypoplastic: specifically,

Purkinje cell loss in Huntington’s disease

Huntington’s disease (HD) is a fatal inherited neurological disorder resulting from the expression of an expanded polyglutamine repeat in the HD gene. The disease primarily affects medium-spiny neurons in the striatum, but a significant reduction of Purkinje cell numbers has also been reported (Schenk and Enters, 1970, Jeste et al., 1984). For example, Rodda (1981) examined three cases of Huntington’s disease with severe cerebellar atrophy and reported an almost complete loss of Purkinje cells.

Purkinje cell loss in Alzheimer’s disease

Alzheimer’s disease is characterized by generalized cerebral cortical atrophy and widespread senile plaques and neurofibrillary tangles. Alzheimer’s patients can also have significant atrophy of the cerebellar vermis, degeneration of Purkinje cells and prominent gliosis within the molecular layer (Sjobeck and Englund, 2001). Patients with severe, final stage Alzheimer’s disease were found to have a 32% decrease in Purkinje cell numbers (Wegiel et al., 1999). Furthermore, reduced Purkinje cell

Purkinje cell loss in multiple system atrophy

Approximately half of patients with multiple system atrophy (MSA) exhibit cerebellar ataxia (Wenning et al., 1997) and cerebellar atrophy that is more pronounced in the vermis than in the hemispheres (Kume et al., 1991, Wenning et al., 1996, Tsuchiya et al., 1998). Microscopical examination reveals marked loss of Purkinje cells (Spokes et al., 1979, Kume et al., 1991, Wenning et al., 1996) with significant sparing of the nodulus (lobule X; Kume et al., 1991, Wenning et al., 1996).

Purkinje cell loss in paraneoplastic cerebellar degeneration

Paraneoplastic neurological syndromes comprise a heterogeneous group of disorders that arise as non-metastatic manifestations of malignancy outside of the nervous system. Signs of neurological damage typically precede the diagnosis of cancer. The underlying etiology of paraneoplastic syndromes is autoimmune. The serum and cerebrospinal fluid of patients with paraneoplastic disease contain antibodies that recognize antigens shared by neuronal and tumor cells. Paraneoplastic cerebellar

Purkinje cell loss due to alcohol

Acute alcohol intoxication produces symptoms that resemble cerebellar dysfunction, including slurred speech and staggering gait. It is not surprising then that a primary site of ethanol toxicity within the central nervous system is in the cerebellum. It has been long been known that alcoholism can result in cerebellar atrophy and loss of Purkinje cells (Neubuerger, 1957, Victor et al., 1959, Lynch, 1960, Allsop and Turner, 1966). The incidence of cerebellar involvement is as high as 40% in the

Conclusions

Patterned Purkinje cell loss has been recognized for almost a century (Thomas, 1905). Patterns of stripes were first clearly described by Wassef et al. (1987). The conclusion from all the studies of Purkinje cell degeneration reviewed above is that topographically-organized cell loss is far more common than usually recognized—indeed, examples in which Purkinje cell loss occurs randomly are scarce! At least four patterns of Purkinje cell death have been described in the literature:

  • The zebrin

Acknowledgements

These studies were supported by studentships from the Alberta Heritage Foundation for Medical Research and the Canadian Institutes of Health Research (JRS) and grants from the Canadian Institutes of Health Research and the Ara Parseghian Foundation for Medical Research (RH).

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