Cell-autonomous and non-cell-autonomous toxicity in polyglutamine diseases

https://doi.org/10.1016/j.pneurobio.2011.10.003Get rights and content

Abstract

Polyglutamine diseases are neurodegenerative disorders caused by expansion of polyglutamine tracts in the coding regions of specific genes. One of the most important features of polyglutamine diseases is that, despite the widespread and in some cases ubiquitous expression of the polyglutamine proteins, specific populations of neurons degenerate in each disease. This finding has led to the idea that polyglutamine diseases are cell-autonomous diseases, in which selective neuronal dysfunction and death result from damage caused by the mutant protein within the targeted neuronal population itself. Development of animal models for conditional expression of polyglutamine proteins, along with new pharmacologic manipulation of polyglutamine protein expression and toxicity, has led to a remarkable change of the current view of polyglutamine diseases as cell-autonomous disorders. It is becoming evident that toxicity in the neighboring non-neuronal cells contributes to selective neuronal damage. This observation implies non-cell-autonomous mechanisms of neurodegeneration in polyglutamine diseases. Here, we describe cell-autonomous and non-cell-autonomous mechanisms of polyglutamine disease pathogenesis, including toxicity in neurons, skeletal muscle, glia, germinal cells, and other cell types.

Highlights

ā–ŗ Polyglutamine diseases are caused by expansion of the CAG repeat in specific genes. ā–ŗ Polyglutamine proteins are expressed both in neuronal and non-neuronal cells. ā–ŗ Polyglutamine expansion is extremely and selectively neurotoxic. ā–ŗ Neuronal death is the result of cell-autonomous and non-cell-autonomous toxicity. ā–ŗ Primary damage in skeletal muscle, glia and germ cells contributes to pathogenesis.

Introduction

Polyglutamine (polyQ) diseases represent a family of nine neurodegenerative disorders, which include Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxia type 1, 2, 3, 6, 7, and 17. These disorders are caused by expansion of the trinucleotide CAG tandem repeat, encoding a polyQ tract, in the exonic regions of specific genes; these genes are huntingtin, atrophin-1, androgen receptor, ataxin-1, ataxin-2, ataxin-3, CACNA1A, ataxin-7, and the TATA-binding protein, respectively.

PolyQ diseases share several features. Even if the mutant protein is expressed beginning in early development, polyQ diseases are late-onset disorders. The length of the polyQ tracts influences disease presentation and predicts greater severity and younger age of onset with increasing repeat lengths (Andrew et al., 1993, Snell et al., 1993). Similar to other tandem repeat disorders, polyQ diseases show ā€œgenetic anticipation,ā€ with the following generation likely to inherit a longer repeat than the previous one, thereby resulting in increased disease severity with earlier onset. Expanded polyQ tracts confer to the mutant protein the tendency to accumulate as insoluble material, which appears in the form of inclusions and micro-aggregates or oligomers. Despite polyQ proteins being expressed in both neuronal and non-neuronal cells, neurons are extremely and selectively sensitive to the accumulation of expanded polyQ proteins. Furthermore, only specific types of neurons degenerate in each polyQ disease. Selective neuronal vulnerability has long been interpreted to be the result of cell-autonomous toxicity due to the expression of mutant protein, possibly exacerbated by age-dependent generation of a toxic environment. However, this scenario has recently been challenged by the discovery that toxic pathways that lead to neuronal damage are influenced by damage occurring in non-neuronal cells. This finding suggests that in addition to cell-autonomous toxicity in neuronal cells, damage in non-neuronal cells, such as muscle and glial cells, are likely to play a critical role in the pathogenesis of polyQ diseases. Non-cell-autonomous pathways of degeneration have been described in neurodegenerative conditions such as amyotrophic lateral sclerosis and Parkinson's disease (reviewed by Ilieva et al., 2009, Lobsiger and Cleveland, 2007). Here, we describe cell-autonomous and non-cell-autonomous mechanisms of neurodegeneration in spinal and bulbar muscular atrophy and Huntington's disease as models of polyQ diseases.

Section snippets

Clinical features of SBMA

SBMA is characterized by the degeneration and loss of lower motor neurons in the brainstem and spinal cord, which manifest clinically as progressive weakness, with atrophy and fasciculation of proximal limb and bulbar muscles (Kennedy et al., 1968). Distal muscle weakness and atrophy are observed in the arms more than the legs. The exordium of the disease usually manifests with cramps, hand tremor and fatigue, followed several years later by muscle weakness, which disrupts patientsā€™ ability to

Clinical features of HD

The most common polyQ disease, HD is an autosomal dominant neurodegenerative disorder that manifests in both men and women. The disease is characterized by motor dysfunction, which initiates with chorea, dystonia, and movement incoordination, and culminates in loss of the ability to move, bradykinesia, and rigidity in the final stages of the disease (Paradisi et al., 2008, Rao et al., 2008, Thompson et al., 1988). These symptoms are associated with impairment of cognitive functions, such as

Clinical features of SCA

Expansions of polyQ tracts in six different genes, known as ataxin-1 (Orr et al., 1993), ataxin-2 (Imbert et al., 1996), ataxin-3 (Kawaguchi et al., 1994), CACNA1A (Zhuchenko et al., 1997), ataxin-7 (David et al., 1997), and the TATA-binding protein (TBP) (Nakamura et al., 2001), are responsible for six types of autosomal dominant SCAs, designated SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17, respectively. SCAs are late-onset and progressive neurological disorders characterized by the loss of motor

Mechanisms underlying cell-autonomous and non-cell-autonomous toxicity in polyQ diseases

The reason why neurons are primarily damaged by the expression of polyQ protein remains an enigma, as the expression of the majority of polyQ proteins is not restricted to neurons. Several factors can contribute to selective neuronal vulnerability, including specific changes in expression levels, subcellular localization, and alteration of folding and function of polyQ proteins.

Concluding remarks

It is now widely accepted that polyQ diseases result from combined cell-autonomous and non-cell-autonomous pathways of toxicity, which ultimately lead to neuronal dysfunction and death. In addition to neuronal toxicity, non-neuronal cells are also subjected to polyQ protein toxicity, in a cell-autonomous and non-cell-autonomous fashion. Clarification of the contribution of cell-autonomous and non-cell-autonomous toxicity in polyQ disease is needed from a therapeutic point of view. Indeed, if

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgments

We apologize to those authors whose work was not cited in this review due to space limitations. We thank N. Nedelsky for comments and editing of the manuscript. This work was supported by Marie Curie Reintegration grants (FP7-256448 to M.P. and FP7-276981 to F.S.), Telethon-Italy (GGP10037), the Kennedy's Disease Association, Fondation Thierry Latran (AAP091102), and the Muscular Dystrophy Association (196646).

References (310)

  • R.B. Fishman et al.

    Local perineal implants of anti-androgen block masculinization of the spinal nucleus of the bulbocavernosus

    Brain Res. Dev. Brain Res.

    (1992)
  • L.R. Gauthier et al.

    Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules

    Cell

    (2004)
  • J.D. Godin et al.

    Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis

    Neuron

    (2010)
  • J.N. Goldenberg et al.

    Testosterone therapy and the pathogenesis of Kennedy's disease (X-linked bulbospinal muscular atrophy)

    J. Neurol. Sci.

    (1996)
  • A.O. Goodman et al.

    The metabolic profile of early Huntington's disease ā€“ a combined human and transgenic mouse study

    Exp. Neurol.

    (2008)
  • X. Gu et al.

    Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice

    Neuron

    (2005)
  • D. Guidetti et al.

    X-linked bulbar and spinal muscular atrophy, or Kennedy disease: clinical, neurophysiological, neuropathological, neuropsychological and molecular study of a large family

    J. Neurol. Sci.

    (1996)
  • M.C. Guyot et al.

    Quantifiable bradykinesia, gait abnormalities and Huntington's disease-like striatal lesions in rats chronically treated with 3-nitropropionic acid

    Neuroscience

    (1997)
  • G. Haase et al.

    Adenovirus-mediated transfer of the neurotrophin-3 gene into skeletal muscle of pmn mice: therapeutic effects and mechanisms of action

    J. Neurol. Sci.

    (1998)
  • K.F. Hauser et al.

    Androgen action in fetal mouse spinal cord cultures: metabolic and morphologic aspects

    Brain Res.

    (1987)
  • H.A. Al-Shamma et al.

    Brain-derived neurotrophic factor regulates expression of androgen receptors in perineal motoneurons

    Proc. Natl. Acad. Sci. U.S.A.

    (1997)
  • A.A. Amato et al.

    Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene

    Neurology

    (1993)
  • S.E. Andrew et al.

    The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease

    Nat. Genet.

    (1993)
  • I. Araki et al.

    Target-dependent hormonal control of neuron size in the rat spinal nucleus of the bulbocavernosus

    J. Neurosci.

    (1991)
  • M. Arrasate et al.

    Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death

    Nature

    (2004)
  • E.H. Aylward et al.

    Striatal volume contributes to the prediction of onset of Huntington disease in incident cases

    Biol. Psychiatry

    (2011)
  • N.A. Aziz et al.

    Weight loss in Huntington disease increases with higher CAG repeat number

    Neurology

    (2008)
  • M. Azzouz et al.

    VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model

    Nature

    (2004)
  • K. Bacos et al.

    Islet beta-cell area and hormone expression are unaltered in Huntington's disease

    Histochem. Cell Biol.

    (2008)
  • H. Banno et al.

    Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy

    Ann. Neurol.

    (2009)
  • F. Battaglia et al.

    Kennedy's disease initially manifesting as an endocrine disorder

    J. Clin. Neuromuscul. Dis.

    (2003)
  • B.J. Baumgartner et al.

    Targeted transduction of CNS neurons with adenoviral vectors carrying neurotrophic factor genes confers neuroprotection that exceeds the transduced population

    J. Neurosci.

    (1997)
  • S. Bhasin et al.

    Testosterone replacement increases fat-free mass and muscle size in hypogonadal men

    J. Clin. Endocrinol. Metab.

    (1997)
  • U. Bichelmeier et al.

    Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence

    J. Neurosci.

    (2007)
  • M. Bjorkqvist et al.

    The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient beta-cell mass and exocytosis

    Hum. Mol. Genet.

    (2005)
  • S.C. Bodine et al.

    Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo

    Nat. Cell Biol.

    (2001)
  • R.A. Bodner et al.

    Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases

    Proc. Natl. Acad. Sci. U.S.A.

    (2006)
  • T.W. Boesgaard et al.

    Huntington's disease does not appear to increase the risk of diabetes mellitus

    J. Neuroendocrinol.

    (2009)
  • E. Bogaert et al.

    Vascular endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative diseases

    Muscle Nerve

    (2006)
  • N.I. Bohnen et al.

    Decreased striatal monoaminergic terminals in Huntington disease

    Neurology

    (2000)
  • J. Bradford et al.

    Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

    Proc. Natl. Acad. Sci. U.S.A.

    (2009)
  • S.M. Breedlove et al.

    Hormone accumulation in a sexually dimorphic motor nucleus of the rat spinal cord

    Science

    (1980)
  • S.M. Breedlove et al.

    Sexually dimorphic motor nucleus in the rat lumbar spinal cord: response to adult hormone manipulation, absence in androgen-insensitive rats

    Brain Res.

    (1981)
  • I.G. Brodsky et al.

    Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men ā€“ a clinical research center study

    J. Clin. Endocrinol. Metab.

    (1996)
  • B.P. Brooks et al.

    A cell culture model for androgen effects in motor neurons

    J. Neurochem.

    (1998)
  • D. Brown et al.

    Mouse model of testosterone-induced muscle fiber hypertrophy: involvement of p38 mitogen-activated protein kinase-mediated Notch signaling

    J. Endocrinol.

    (2009)
  • T.B. Brown et al.

    Neocortical expression of mutant huntingtin is not required for alterations in striatal gene expression or motor dysfunction in a transgenic mouse

    Hum. Mol. Genet.

    (2008)
  • B. Burnett et al.

    The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity

    Hum. Mol. Genet.

    (2003)
  • M.E. Busse et al.

    Use of hand-held dynamometry in the evaluation of lower limb muscle strength in people with Huntington's disease

    J. Neurol.

    (2008)
  • B. Cannon et al.

    Brown adipose tissue: function and physiological significance

    Physiol. Rev.

    (2004)
  • Cited by (34)

    • Neuronal chloride transporters in neurodegenerative diseases

      2020, Neuronal Chloride Transporters in Health and Disease
    • Impaired Local Translation of Ī²-actin mRNA in Ighmbp2-Deficient Motoneurons: Implications for Spinal Muscular Atrophy with respiratory Distress (SMARD1)

      2018, Neuroscience
      Citation Excerpt :

      This opens the view on cellular mechanisms in non-neuronal cells affected by Ighmbp2 deficiency which in addition might induce motoneuron death. Non-cell-autonomous disease mechanisms are already described for several forms of amyotrophic lateral sclerosis caused by mutations in SOD1 (Clement et al., 2003) and TDP-43 (Haidet-Phillips et al., 2011; Meyer et al., 2014; Lee et al., 2016) as well as spinal and bulbar muscular atrophy (SBMA) (Sambataro and Pennuto, 2012). These non-cell-autonomous mechanisms could be an indication of affected trophic support leading to motoneuron death.

    • Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

      2017, Cell Reports
      Citation Excerpt :

      Uncovering these mechanisms would provide insights into the molecular basis of neurodegeneration and offer clues for the development of neuroprotective therapies. In contrast to neurodegenerative diseases such as Parkinsonā€™s, Huntingtonā€™s, and amyotrophic lateral sclerosis (ALS), in which both cell-autonomous and non-cell-autonomous pathways contribute to degeneration of vulnerable neurons (BoillĆ©e et al., 2006; Michel et al., 2016; Sambataro and Pennuto, 2012), the cell-autonomous origin of motor neuron death in spinal muscular atrophy (SMA) is well established (Fletcher et al., 2017; Gogliotti et al., 2012; Martinez et al., 2012; McGovern et al., 2015; Simon et al., 2016). Thus, SMA provides an ideal context to identify cellular pathways and key drivers of selective neurodegeneration.

    • Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis

      2014, Neurobiology of Aging
      Citation Excerpt :

      Androgens have anabolic effects on skeletal muscle (Solomon and Bouloux, 2006; West and Phillips, 2010) and have trophic effects on motor neurons (Cary and La Spada, 2008). However, androgens exert detrimental effects in pathologic conditions, such as SBMA (Sambataro and Pennuto, 2012). To verify whether androgens affect skeletal muscle homeostasis in the context of mutant SOD1-induced ALS, we analyzed skeletal muscle pathology by hematoxylin and eosin staining in hSOD1-G93A mice.

    View all citing articles on Scopus
    View full text