Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, Shang Y, Oldham MC, Martens LH, Gao F, Coppola G, Sloan SA, Hsieh CL, Kim CC, Bigio EH, Weintraub S, Mesulam MM, Rademakers R, Mackenzie IR, Seeley WW, Karydas A, Miller BL, Borroni B, Ghidoni R, Farese RV Jr, Paz JT, Barres BA, Huang EJ. Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell. 2016 May 5;165(4):921-35. Epub 2016 Apr 21 PubMed.

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Comments

  1. This recent paper by Lui and colleagues provides valuable insight into how progranulin deficiency causes neurodegenerative disease. This study shows that progranulin deficiency causes activation of microglia and that the complement system is at least partly responsible for neurodegeneration in the complete gene knockout mouse model. How directly or uniquely progranulin is involved in this process, however, is still unclear. It is known that complete loss of progranulin results in a lysosomal storage disease (LSD) called neuronal ceroid lipofuscinosis, and various LSDs caused by deficiency of multiple other proteins, such as cathepsin D (Partanen et al., 2008), NPC1 (Yamada et al., 2001), glucocerebrosidase (Farfel-Becker et al., 2011), and beta-hexosaminidase (Sargeant et al., 2011) also result in relatively selective neurodegeneration, neuronal cell death, and neuroinflammation within the VPM/VPL of the murine thalamus (Sargeant 2016). It is therefore possible the effects observed in this paper result from a lysosomal defect that can be caused by deficits in a wide range of lysosomal proteins. These observations, along with other lines of evidence (such as lysosomal storage in FTD caused by CHMP2B mutation [Sep 2015 news; Clayton et al., 2015]) show targeting of lysosomal function in late-onset neurodegenerative disease could offer a feasible therapeutic strategy.

    References:

    Partanen S, Haapanen A, Kielar C, Pontikis C, Alexander N, Inkinen T, Saftig P, Gillingwater TH, Cooper JD, Tyynelä J. Synaptic changes in the thalamocortical system of cathepsin D-deficient mice: a model of human congenital neuronal ceroid-lipofuscinosis. J Neuropathol Exp Neurol. 2008 Jan;67(1):16-29. PubMed.

    Yamada A, Saji M, Ukita Y, Shinoda Y, Taniguchi M, Higaki K, Ninomiya H, Ohno K. Progressive neuronal loss in the ventral posterior lateral and medial nuclei of thalamus in Niemann-Pick disease type C mouse brain. Brain Dev. 2001 Aug;23(5):288-97. PubMed.

    Farfel-Becker T, Vitner EB, Pressey SN, Eilam R, Cooper JD, Futerman AH. Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease. Hum Mol Genet. 2011 Apr 1;20(7):1375-86. Epub 2011 Jan 20 PubMed.

    Sargeant TJ, Wang S, Bradley J, Smith NJ, Raha AA, McNair R, Ziegler RJ, Cheng SH, Cox TM, Cachón-González MB. Adeno-associated virus-mediated expression of β-hexosaminidase prevents neuronal loss in the Sandhoff mouse brain. Hum Mol Genet. 2011 Nov 15;20(22):4371-80. Epub 2011 Aug 18 PubMed.

    Sargeant TJ. Commentary: Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice. Front Aging Neurosci. 2016;8:11. Epub 2016 Feb 3 PubMed.

    Clayton EL, Mizielinska S, Edgar JR, Nielsen TT, Marshall S, Norona FE, Robbins M, Damirji H, Holm IE, Johannsen P, Nielsen JE, Asante EA, Collinge J, FReJA consortium, Isaacs AM. Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology. Acta Neuropathol. 2015 Oct;130(4):511-23. Epub 2015 Sep 10 PubMed.

    View all comments by Timothy Sargeant

  2. In this paper, Dr. Lui and co-workers demonstrated that progranulin (PGRN) deficiency facilitated synaptic pruning resulting from increased C1qa production in cultured microglia and in mice.

    PGRN haploinsufficiency, resulting from a heterozygous mutation in the PGRN gene (GRN), causes frontotemporal lobar degeneration (FTLD) characterized by cytoplasmic inclusions containing TAR DNA binding protein 43 (Baker et al., 2006; Cruts et al., 2006). Patients with a homozygous mutation in GRN exhibit neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease (Smith et al., 2012).

    Previous studies indicated a role for PGRN in lysosomal function (Tanaka et al., 2013; Zhou et al., 2015). Aged, PGRN-deficient mice present excessive neuroinflammation in the ventral thalamus that is likely due to lysosomal defects in the brain because NCL model mice are particular vulnerable in this region of the brain (Tanaka et al., 2014; Kielar et al., 2007; Partanen et al., 2008; von Schantz et al., 2009). 

    In the present study, C1qa production and synaptic pruning increased in the lysosome-compromised, PGRN-deficient primary microglia. Moreover, these increases occurred in the ventral thalamus of aged and lysosome-defective PGRN-deficient mice, but not in younger ones. Since C1qa production also increases in mouse models of lysosomal storage diseases such as mucopolysaccharidoses I and IIIB (Ohmi et al., 2003), increased C1qa production and synaptic pruning activity in PGRN-deficient microglia might result from lysosomal defects. Studying synaptic pruning and C1qa production in the ventral thalamus of other NCL model mice might be useful to elucidate how PGRN regulates synaptic pruning.

    Importantly, loss of C1qa could partially suppress pathological changes in PGRN-deficient mice. This suggests that therapies targeting the complement pathway in microglia might improve neurodegenerative diseases resulting from PGRN deficiency or lysosomal defects, though the relationship between the latter and increased C1qa production remains to be elucidated. Further investigation into the regulation of the complement pathway in microglia might lead to new strategies to mitigate neurodegeneration.

    References:

    Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006 Aug 24;442(7105):916-9. PubMed.

    Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006 Aug 24;442(7105):920-4. PubMed.

    Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF, Sims KB, Lewis J, Lin WL, Dickson DW, Dahl HH, Bahlo M, Berkovic SF. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet. 2012 Jun 8;90(6):1102-7. PubMed.

    Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M. Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice. Neuroscience. 2013 Oct 10;250:8-19. PubMed.

    Zhou X, Sun L, Bastos de Oliveira F, Qi X, Brown WJ, Smolka MB, Sun Y, Hu F. Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol. 2015 Sep 14;210(6):991-1002. PubMed.

    Tanaka Y, Chambers JK, Matsuwaki T, Yamanouchi K, Nishihara M. Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice. Acta Neuropathol Commun. 2014 Jul 15;2:78. PubMed.

    Kielar C, Maddox L, Bible E, Pontikis CC, Macauley SL, Griffey MA, Wong M, Sands MS, Cooper JD. Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2007 Jan;25(1):150-62. Epub 2006 Oct 12 PubMed.

    von Schantz C, Kielar C, Hansen SN, Pontikis CC, Alexander NA, Kopra O, Jalanko A, Cooper JD. Progressive thalamocortical neuron loss in Cln5 deficient mice: Distinct effects in Finnish variant late infantile NCL. Neurobiol Dis. 2009 May;34(2):308-19. PubMed.

    Partanen S, Haapanen A, Kielar C, Pontikis C, Alexander N, Inkinen T, Saftig P, Gillingwater TH, Cooper JD, Tyynelä J. Synaptic changes in the thalamocortical system of cathepsin D-deficient mice: a model of human congenital neuronal ceroid-lipofuscinosis. J Neuropathol Exp Neurol. 2008 Jan;67(1):16-29. PubMed.

    Ohmi K, Greenberg DS, Rajavel KS, Ryazantsev S, Li HH, Neufeld EF. Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1902-7. Epub 2003 Feb 7 PubMed.

    View all comments by Yoshinori Tanaka

  3. This study is very novel as it demonstrates a role for progranulin in regulating lysosomal function and complement system activation in microglia. The authors further showed that complement activation leads to circuit-specific pruning of synapses by microglia. The data is consistent with previous findings that progranulin is essential for proper lysosomal function during aging and that progranulin loss leads to microglial activation and proinflammatory phenotypes. Microglial activation and lysosomal dysfunction have also been known to be implicated in FTLD caused by progranulin mutations.

    This study also suggests that complement protein levels in the CSF correlate with the decline on the MMSE in FTLD-GRN mutant carriers, indicating that CSF complement might be used as a biomarker for this disorder. Interestingly, this CSF change is not seen in AD patients, supporting disease specificity of complement activation in FTLD. Deleting the C1qa gene partially rescued microglial phenotypes in GRN-/- mice, indicating that complement inhibition could potentially be beneficial for FTLD patients with PGRN mutations.

    The connection between lysosomal dysfunction and complement activation seems to be unclear at present. The authors did show that GRN-/- microglia are more efficient in processing materials via the endolysosomal pathway and suggest that this might facilitate lysosomal processing and activation of the complement protein C3. However, the upregulation of C1qa and C3 also seem to be at the transcriptional level—how progranulin loss leads to transcriptional upregulation of complement factors is still unclear. Likewise, how progranulin regulates lysosomal function during aging is still a mystery.

    View all comments by Fenghua Hu

  4. This is a very interesting paper using sophisticated techniques to explore the potential role of progranulin in suppression of microglial activation. The association of genetic mutations leading to low levels of progranulin in some neurological diseases make this an important area to investigate. The authors present transcriptome analyses and immunohistochemical data that show brain region-specific increases in some complement components as well as increased microglial lysosomal size and divergent morphology with aging in progranulin deficit mice. Experiments with BSA-conjugated dye (DQ-BSA) were interpreted to indicate that the Grn-/- microglia are more active (i.e., ingest cargo more readily and more efficiently degrade it). A major and important conclusion of the paper is that Grn reduction leads to impaired regulation of the microglial response to injury (or aging) and thus enhanced synaptic pruning (preferentially of interneuron synapses) leading to hyperactivity in injured or aging animals.

    While an experimentally beautiful paper, the concluded link between greater C3 in the lysosomes and synaptic pruning as suggested by the authors in the results and discussion will require more mechanistic analysis, although indeed there is no need for the ascribed link between these two observations for the validity of their major observation. The authors try to connect intracellular cleavage of C3 in the microglia and subsequent secretion of the cleaved product iC3b with enhanced synaptic pruning. It should be clarified that the activation of complement through C1 (a macromolecular complex comprised of C1q, C1r, and Cls), ultimately leads to the cleavage of C3 to expose the C3 thioester enabling covalent attachment to the activating component, thereby “tagging” it for phagocytosis. If the proposed intracellularly cleaved C3 does not bind immediately to a protein (or sugar) moiety, that reactive thioester binds water and, even if then released from the cell, can no longer covalently bind a target (an extracellular neuronal synapse), tagging it for CR3-mediated elimination by the microglia. As a result, if C3 is cleaved within the lysosome (which can occur by enzymes other than the complement generated C3 cleaving enzyme, as the authors refer to) it will be inactive (in terms of tagging a synapse) by the time it reaches the extracellular space. Rather than the internally cleaved C3 as the mediator in synapse elimination, since C3 is known to be (and verified by the authors) upregulated in the injured brain, there should be plenty of extracellular C3 to become cleaved by the complement pathway at the synapse. Thus, an intriguing future investigation is to identify how the “tagged” synapse became altered to induce binding of C1 and thus activation of the system. In addition, it will be interesting to see if C3a, the smaller C3 cleavage fragment, is having an effect in this system.

    A second consideration in the mechanistic analysis (which is critical for designing a successful therapeutic intervention) is that much of the neuronal circuit alternations and behavioral aberrations could be due not solely to the synapse loss, but also to the generation of C5a and its proinflammatory activities, which would amplify the proinflammatory activation state of local microglia. This could be investigated by assessing synapse loss and behavioral alterations in C5aR-/- animals. The generation of C5a and its consequences certainly should be considered by the field while moving forward in any additional studies of complement activation in the brain, as selective intervention at various points in this pathway will likely be critical for a successful therapeutic.

    View all comments by Andrea Tenner

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